On January 31, 2022 Viracta Therapeutics, Inc. (Nasdaq: VIRX), a precision oncology company targeting virus-associated malignancies, reported that the first patient has been dosed in the multinational Phase 1b/2 trial of its all-oral combination product, Nana-val (nanatinostat and valganciclovir), in patients with Epstein-Barr virus-positive (EBV+) recurrent or metastatic nasopharyngeal carcinoma (R/M NPC) and other advanced EBV+ solid tumors (Press release, Viracta Therapeutics, JAN 31, 2022, View Source [SID1234607522]). The trial is designed to evaluate the safety and preliminary efficacy of Nana-val alone and in combination with the PD-1 inhibitor pembrolizumab.

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"The initiation of dosing in this clinical trial represents an important milestone for Viracta and is a critical step in potentially expanding the clinical applicability of the targeted all-oral Nana-val combination beyond lymphoma," said Lisa Rojkjaer, M.D., Chief Medical Officer of Viracta. "Advanced NPC patients have poor outcomes and are in urgent need of effective treatment options. We are looking forward to evaluating the clinical profile of this novel combination therapy and exploring potential synergies with a PD-1 inhibitor."

The Phase 1b/2 trial (NCT05166577) is an open-label, multinational trial evaluating Nana-val alone and in combination with pembrolizumab. The Phase 1b dose escalation portion is designed to evaluate safety and to determine the recommended Phase 2 dose (RP2D) of Nana-val in patients with EBV+ R/M NPC. In Phase 2, up to sixty patients with EBV+ R/M NPC will be randomized to receive Nana-val at the RP2D with or without pembrolizumab, to evaluate safety, overall response rate, and potential pharmacodynamic markers. Additionally, patients with other advanced EBV+ solid tumors will be enrolled to receive Nana-val at the RP2D in a Phase 1b dose expansion cohort.

About Nana-Val (Nanatinostat and Valganciclovir)

Nanatinostat (VRx-3996) is an orally available histone deacetylase (HDAC) inhibitor being developed by Viracta. Nanatinostat selectively inhibits specific isoforms of Class I HDACs, an activity that is key to inducing viral genes epigenetically silenced in EBV-associated malignancies. Nanatinostat is currently being investigated in combination with the antiviral agent valganciclovir as an all-oral combination therapy, Nana-Val, in various subtypes of EBV-associated malignancies. Ongoing trials include a pivotal global, multicenter, open-label Phase 2 basket trial in multiple subtypes of relapsed/refractory EBV+ lymphoma (NAVAL-1) as well as a multinational Phase 1b/2 trial in patients with EBV+ recurrent or metastatic nasopharyngeal carcinoma and other EBV+ solid tumors.

About EBV-Associated Cancers

Approximately 90% of the world’s adult population is infected with Epstein-Barr virus (EBV), which persists as a life-long latent infection and remains dormant in cell nuclei. Cells containing latent EBV are increasingly susceptible to malignant transformation. EBV infection is directly linked to the development of multiple forms of human lymphoid and epithelial cancers contributing to approximately 2% of all new cancer cases globally. The lack of approved therapies for EBV+ cancers creates a pressing unmet medical need as these malignancies have poor prognoses and are responsible for approximately 180,000 annual deaths.

On January 30, 2022 Akeso, Inc. (9926.HK) reported that the Ligufalimab (CD47 monoclonal antibody, research and development code: AK117, the novel immuno-oncology drug independently developed by the Company) and Ivonescimab (PD-1/VEGF bi-specific antibody, research and development code: AK112) has obtained approval from the Center for Drug Evaluation (CDE) of the National Medical Products Administration of the People’s Republic of China (”China”) to initiate a phase II clinical trial with chemotherapy as first-line therapy for unresectable locally advanced or metastatic triplenegative breast cancer (Press release, Akeso Biopharma, JAN 30, 2022, View Source [SID1234607495]).

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This clinical trial is an open and multi-center phase II clinical trial, which plans to include patients who have not received systemic anti-tumor therapy, are not suitable for radical surgical resection or local therapy, or subjects with locally advanced or metastatic triple-negative breast cancer whose disease progresses after surgical resection or local therapy.

Breast cancer is the most prevalent malignant tumor in women worldwide and in China, among which triple-negative breast cancer (that is, negative for progesterone receptor, estrogen receptor and human epidermal growth factor receptor 2) is highly aggressive and has a high recurrence rate, with a relatively poor prognosis. It is the subtype with the highest recurrence rate and mortality in breast cancer, accounting for approximately 15% of all breast cancers.

Related studies have shown that the mechanisms by which tumor cells evade the innate and adaptive immune systems play a key role in the occurrence and development of recurrent and/or metastatic tumors. An important mechanism of immune escape in triple-negative breast cancer is the expression of CD47. CD47 inhibits the phagocytosis of macrophages by releasing a ”don’t eat me” signal, and at the same time suppresses adaptive immunity by interacting with dendritic cells.

Under the tumor microenvironment, there is a strong correlation between VEGF and PD-1 expression. Therefore, the use of a bi-specific antibody to block PD-1 and VEGF simultaneously can provide a type of drug with more targets in the tumor microenvironment.

Related studies have also shown that the up-regulation of CD47 can inhibit the phagocytosis of macrophages and the anti-tumor effect of VEGF/VEGFR inhibitors. It can also induce the up-regulation of CD47 during anti-angiogenesis therapy. Therefore, blocking both VEGF and CD47 can effectively inhibit the immunosuppressive pathway induced by antiangiogenesis therapy (up-regulation of CD47) while enhancing the phagocytosis of macrophages to improve the anti-tumor efficacy.

Therefore, the combination therapy of Ivonescimab and Ligufalimab is expected to activate both innate and adaptive immune pathways and enhance the targeted recognition of tumors by the immune system, which can create a synergy effect of immunity, anti-angiogenesis and chemotherapy. It is expected to achieve better anti-tumor effects in subjects with advanced triple-negative breast cancer.

On January 30, 2022 Akeso, Inc. (9926.HK) reported that the first patient was dosed in a Phase III registrational clinical trial of the Company’s novel immuno-oncology drug, Ivonescimab (PD-1/VEGF bi-specific antibody, AK112), combined with chemotherapy versus placebo combined with chemotherapy for the treatment of locally advanced or metastatic non-squamous non-small cell lung cancer (nsq-NSCLC) with EGFR mutation failed after EGFR-TKI treatment (Press release, Akeso Biopharma, JAN 30, 2022, View Source [SID1234607496]).

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This clinical trial is the world’s first bi-specific antibody for the Phase III clinical trial of EGFR-TKI resistant NSCLC, and is also an important development of Ivonescimab in the field of lung cancer.

This clinical trial is a randomized, double-blind, multi-center Phase III clinical study with approximately 320 Chinese subjects planned to be enrolled. The purpose of the study is to evaluate the efficacy and safety of Ivonescimab combined with pemetrexed + carboplatin and placebo combined with pemetrexed + carboplatin in the treatment of patients with advanced nsq-NSCLC resistant to EGFR-TKI. The primary endpoint of the study is progression-free survival (PFS) assessed by IRRC.

Lung cancer is a common malignant tumor with high incidence and high mortality in the world, with the number of new lung cancer cases in the world exceeding 2,200,000 in 2020, and the number of new cases in China exceeding 810,000. By type, NSCLC accounts for about 85% of lung cancer, of which about 75% is non-squamous cell NSCLC, and about 70% of NSCLC patients are diagnosed at an advanced stage (Phase IIIB/IV).

For patients with EGFR mutation or ALK fusion mutation-positive NSCLC, although targeted therapy is a first-line standard therapy, issue of drug resistance has become increasingly prominent, and if resistant to targeted therapy, platinum-based chemotherapy remains the most important treatment method, and the existing treatment options cannot effectively meet clinical needs.

”Immunotherapy + anti-angiogenesis” has proven its combined advantages in several worldrenowned studies. As anti-angiogenic therapy can normalize tumor blood vessels and make the tumor microenvironment more suitable for immunotherapy, Immunosuppressants combined with anti-angiogenic drugs has a synergistic anti-tumor effect. This combination is widely appreciated. Lung cancer treatment is the main exploration direction of the above combination therapy; The ”immune + anti-angiogenesis” combination therapy under development in the world for first-line and later-line treatment of NSCLC has shown promising anti-tumor activity and clinical application prospects.

Ivonescimab also has the effect of stimulating antitumor immune responses and inhibiting tumor angiogenesis. Because of the immunosuppressive effect of the overexpressed VEGF in the tumor microenvironment, if a bi-specific antibody can be used to block both PD-1 and VEGF, theoretically the synergistic anti-tumor effect of anti-PD-1 antibody and anti-VEGF antibody can be realized. As a result, Ivonescimab with chemotherapy for the treatment of EGFR-TKI resistant NSCLC is expected to achieve better clinical efficacy and safety than other therapies.

In a number of early clinical studies in Australia and China, Ivonescimab has demonstrated good safety and tolerability in the treatment of various types of lung cancer, including NSCLC and small cell lung cancer (SCLC), with excellent anti-tumor effects. In addition to this study, Ivonescimab’s Phase III clinical trial for the first-line treatment of PD-L1positive NSCLC and Ivonescimab’s Phase III clinical trial for the first-line treatment of extensive SCLC will commence soon. The Phase Ib/II clinical study of Cadonilimab (PD-1/ CTLA-4 bi-specific antibody, AK104) plus Ivonescimab and/or in combination with chemotherapy for the treatment of advanced non-small cell lung cancer (NSCLC) has also been carried out successively.

On January 30, 2022 Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, "Eisai") reported that LENVIMA (generic name: lenvatinib mesylate), the multiple receptor tyrosine kinase inhibitor discovered by Eisai, in combination with Merck & Co., Inc., Kenilworth, N.J., U.S.A.’s KEYTRUDA (generic name: pembrolizumab) has been approved in Taiwan for the first-line treatment of patients with advanced renal cell carcinoma (RCC) (Press release, Eisai, JAN 30, 2022, View Source [SID1234607492]). This marks the first approval for LENVIMA which will be used in combination with KEYTRUDA for advanced RCC in Asia.

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The approval is based on results from the CLEAR (Study 307)/KEYNOTE-581 trial evaluating the combination for the first-line treatment of patients with advanced RCC. These results were presented at the 2021 Genitourinary Cancers Symposium (ASCO GU) and simultaneously published in the New England Journal of Medicine. 1 In this trial, LENVIMA plus KEYTRUDA demonstrated statistically significant improvements in the primary efficacy outcome measure of progression-free survival (PFS), as well as the key secondary efficacy outcome measures of overall survival (OS) and objective response rate (ORR) versus sunitinib. For PFS, LENVIMA plus KEYTRUDA reduced the risk of disease progression or death by 61% (HR=0.39 [95% CI: 0.32-0.49]; p<0.0001) with a median PFS of 23.9 months versus 9.2 months for sunitinib. For OS, LENVIMA plus KEYTRUDA reduced the risk of death by 34% (HR=0.66 [95% CI: 0.49-0.88]; p=0.0049) versus sunitinib. Additionally, the confirmed ORR was 71% (95% CI: 66-76) (n=252) for patients who received LENVIMA plus KEYTRUDA versus 36% with sunitinib (95% CI: 31-41) (n=129). LENVIMA plus KEYTRUDA achieved a complete response (CR) rate of 16% and partial response (PR) rate of 55% versus a CR rate of 4% and a PR rate of 32% for those who received sunitinib. 2 In this trial, the five most common adverse reactions (any grade) observed in the LENVIMA plus KEYTRUDA combination arm were fatigue, diarrhea, musculoskeletal disorders, hypothyroidism and hypertension. 2

Worldwide, it is estimated there were more than 430,000 new cases of kidney cancer diagnosed and more than 180,000 deaths from the disease in 2020. 3 In Taiwan, there were more than 1,400 new cases and more than 600 deaths in 2018. 4 Renal cell carcinoma is by far the most common type of kidney cancer; about nine out of 10 kidney cancer diagnoses are RCC. 5 Most cases of RCC are discovered incidentally during imaging tests for other abdominal diseases. 6 Approximately 30% of patients with RCC will have metastatic disease at diagnosis, and as many as 40% will develop metastases after primary surgical treatment for localized RCC. 7,8　 The prognosis for these patients is poor as survival is highly dependent on the stage at diagnosis, and the five-year survival rate is 12% for patients diagnosed with metastatic disease. 8

Eisai positions oncology as a key therapeutic area and is aiming to discover innovative new medicines with the potential to cure cancer. Eisai is committed to expanding the potential clinical benefits of lenvatinib for cancer treatment, as it seeks to contribute to addressing the diverse needs of, and increasing the benefits provided to, patients with cancer, their families and healthcare professionals.

*In March 2018, Eisai and Merck & Co., Inc., Kenilworth, N.J., U.S.A., through an affiliate, entered into a strategic collaboration for the worldwide co-development and co-commercialization of lenvatinib, both as monotherapy and in combination with the anti-PD-1 therapy pembrolizumab from Merck & Co., Inc., Kenilworth, N.J., U.S.A.

On January 28, 2022 Imugene (ASX: IMU) reported a new clinical trial supply agreement with Roche to evaluate the safety and efficacy of Imugene’s PD1-Vaxx, a B-cell activating immunotherapy, in combination with atezolizumab (Tecentriq), an immune checkpoint inhibitor targeting PD-L1, in patients with non-small cell lung cancer (NSCLC) (Press release, Imugene, JAN 28, 2022, View Source [SID1234607523]).

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The objectives of the phase 1b trial, "An Open Label, Multi-Center, Dose Escalation/Expansion, Phase 1 Study of IMU-201 (PD1-Vaxx), a B-Cell Immunotherapy as monotherapy or in combination with atezolizumab, in Adults with Non-Small Cell Lung Cancer," are to determine safety, efficacy, and optimal dose of PD1-Vaxx in combination with atezolizumab as either first-line therapy in ICI treatmentnaïve NSCLC patients or ICI pretreated patients. The study will be conducted at sites in USA and Australia.

Dual targeting of the PD-1/PD-L1 axis is an area of considerable interest with ongoing clinical results providing treatment options for patients with cancer. Combination with PD1-Vaxx may overcome treatment resistance to ICIs with dual inhibition of the PD-1/PD-L1 axis extending the treatment benefit of atezolizumab. In contrast to combination of two monoclonal antibodies, PD1-Vaxx has the advantage that it induces a unique polyclonal immune response which may increase response rates for the combination therapy.

Tecentriq has previously shown clinically meaningful benefit in various types of lung cancer, with six currently approved indications in the US. In addition to becoming the first approved cancer immunotherapy for adjuvant NSCLC, Tecentriq was also the first approved cancer immunotherapy for front-line treatment of adults with extensive-stage small cell lung cancer (SCLC) in combination with carboplatin and etoposide (chemotherapy). Tecentriq also has four approved indications in advanced NSCLC as either a single agent or in combination with targeted therapies and/or chemotherapies.

"It’s an outstanding accomplishment to see Imugene collaborate with Roche, in combination with our PD1-Vaxx drug. PD1-Vaxx has shown a tolerable safety profile and encouraging efficacy in patients with NSCLC, and we are looking forward to evaluating PD1-Vaxx with atezolizumab in ICI treatment-naïve and pretreated NSCLC patients." said Leslie Chong, Managing Director & Chief Executive Officer of Imugene.

Imugene and Roche have entered into a supply agreement for a period of up to five years for the supply of atezolizumab. Imugene will be the sponsor of the study and will fund the clinical study from existing budgets and resources. Roche will supply atezolizumab for the duration of the study. In accordance with the terms of the supply agreement, all data generated in the performance of the study shall be the property of Imugene as the sponsor and all rights to all inventions and discoveries made or conceived in the course of the study relating to the combination of atezolizumab and PD1-Vaxx shall belong jointly to Roche and Imugene.

About NSCLC
Lung cancer is one of the leading causes of cancer death globally Each year 1.8 million people die as a
result of the disease; this translates into more than 4,900 deaths worldwide every day. Lung cancer
can be broadly divided into two major types: NSCLC and SCLC. NSCLC is the most prevalent type,
accounting for around 85% of all cases.