Summary of recent research progress in the field of cancer (06.13)

Summary of recent research progress in the field of cancer (06.13)

June 13, 2018 Source: WuXi PharmaTech

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1. The risk of disease has dropped by 81% ! FDA approves new leukemia therapy

AbbVie and Genentech have announced that the US FDA has approved the use of the heavy-duty drug Venclexta (venetoclax) in combination with Rituxan (rituximab) for the treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic Lymphoma (SLL) patients.

Chronic lymphocytic leukemia is the most common type of leukemia in adults, with the main disease occurring in the blood and bone marrow. It is estimated that there will be 20,000 new cases in the United States in 2018, and it is currently unable to be cured. Small lymphocytic lymphoma is a disease similar to chronic lymphocytic leukemia, but the main disease occurs in the lymph nodes. For these two types of diseases, patients still lack effective treatment options.

The approved combination therapy is expected to bring hope to patients. Venclexta is a selective BCL-2 inhibitor that inhibits the overexpression of BCL-2 protein in chronic lymphocytic leukemia. This protein plays an important role in the process of programmed cell death, and inhibition of it is expected to reshape the cell's key signaling pathways, allowing cancer cells to self-destruct. Rituxan is a monoclonal antibody against CD20 that is effective in the treatment of non-Hodgkin's lymphoma.

The therapeutic potential of this combination therapy was validated in a phase 3 clinical trial called MURANO. The study enrolled 389 patients with chronic lymphocytic leukemia who had received at least one treatment and divided them into two groups. One group received treatment with betadamustine and Rituxan, and the other received treatment with Venclexta and Rituxan. Studies have shown that the combination of Venclexta and Rituxan significantly reduces the risk of disease progression or death by 81% compared with the standard treatment regimen (HR = 0.19; 95% CI: 0.13-0.28; p < 0.0001). Based on these good data, the FDA officially approved its listing.

2. Pfizer PARP inhibitors are given priority review for advanced breast cancer

Pfizer recently announced that the US FDA has accepted its new drug application (NDA) for talazoparib and granted it priority review. The submission of the NDA is based on the results of the clinical trial EMBRACA. This trial evaluated the efficacy of talazoparib in patients with HER2-negative locally advanced or metastatic breast cancer (MBC) with germline (hereditary) BRCA mutations (gBRCAm) compared to chemotherapy. At the same time, the European Medicines Agency (EMA) also accepted the marketing authorization application (MAA) for talazoparib.

BRCA1 and BRCA2 are human genes that produce proteins involved in DNA repair. When it is mutated, DNA repair may not work properly, leading to the development of certain types of cancer, such as breast cancer. The BRCA mutation can be hereditary (germ cell) or spontaneous (somatic). BRCA1 and BRCA2 mutations account for approximately 25% to 30% of hereditary breast cancer, and 5% to 10% of all breast cancers. It is estimated that approximately 72% of people with hereditary BRCA1 mutations, and about 69% of those with BRCA2 mutations, develop breast cancer before the age of 80.

Talazoparib is a PARP inhibitor that is administered orally once a day. Preclinical studies have shown that talazoparib is highly potent and has a dual mechanism of action, with the potential to induce tumor cell death by blocking PARP enzyme activity and capturing PARP at the site of DNA damage.

The efficacy of Talazoparib in the treatment of breast cancer has been confirmed in clinical trials. The EMBRACA trial evaluated talazoparib and doctor-selected chemotherapy once daily in 431 patients with locally advanced or metastatic triple-negative (TNBC) or hormone receptor-positive (ER+)/HER2- patients with hereditary BRCA1/2 mutations. Efficacy of capecitibine, eribulin, gemcitabine or vinorelbine. The study reached its primary endpoint, demonstrating that talazoparib has superior progression-free survival (PFS) compared to chemotherapy. And PFS benefits were consistent across pre-defined subgroups, including patients with a history of brain metastases, patients who had received chemotherapy, TNBC patients, and HR+ patients.

3. Gilead TCR therapy is expected to treat HPV- positive solid tumors

Recently, Gilead Sciences' Kite Company released early data on clinical Phase 1 trials of T cell receptor (TCR) therapy for HPV-positive solid tumors. Studies have shown that TCR therapy targeting E7 protein of type 16 HPV (HPV-16) can achieve partial tumor remission in some HPV-16 positive cancer patients.

There is a causal relationship between HPV infection and almost all cervical cancer, and it can also lead to a variety of head and neck cancers and anogenital malignancies. HPV-16 is the most common type of HPV in these tumors. At present, the treatment methods for HPV-related tumors not only have a low remission rate, but also have a short remission period.

TCR therapy is an individualized immunotherapy that activates the body's own immune system to recognize and kill specific tumors. It collects T lymphocytes from patients and then expresses native lymphocyte receptors that target specific tumor antigens on the surface of these cells. A protein called E7 is expressed in tumor cells of epithelial cancer caused by HPV. Patients with these tumors will not be able to heal if they relapse after receiving standard therapy or become resistant to therapy.

KITE-439, developed by Kite, is expected to address this condition. It is a TCR therapy that targets E7 protein. In this ongoing clinical phase 1 trial, 8 patients with metastatic HPV-16 positive tumors received T cell therapy expressing E7 TCR. These patients have previously received 3 to 7 systemic cancer therapies. In 6 patients who initially received TCR cell therapy, 90-99% of the cells in the injected T cells expressed E7 TCR, and T cells expressing E7 TCR were still detectable in peripheral blood 6 weeks after treatment. .

The results showed that of the 7 patients who were evaluated, 3 patients had partial tumor remission and 2 patients had stable tumor status. As of the time of data release, the remission period can be up to 9 months. Patients with partial remission are vulvar cancer, oropharyngeal cancer and anal cancer. Two of them have been treated with anti-PD1 immunological checkpoint inhibitors. In addition, the study did not show the toxic side effects of limiting the dose of therapy.

4. PARP inhibitors overcome advanced prostate cancer, significantly prolonging PFS

Recently, AstraZeneca and Merck (MSD) announced data on the development of a new drug, Lynparza (olaparib), for the treatment of metastatic castration-resistant prostate cancer patients (mCRPC). The study showed that Lynparza combined with abiraterone significantly improved median radiographic progression-free survival (rPFS) in patients with mCRPC compared with standard treatment with abiraterone monotherapy.

Prostate cancer is the second most common cancer in men. In 2015, there were approximately 1.6 million new diagnoses worldwide and the mortality rate was high. Prostate cancer is often driven by androgen, including testosterone. In mCRPC, although patients use androgen-deprivation therapy to block the effects of androgens, prostate cancer still grows and spreads to other parts of the body. Approximately 10-20% of patients with advanced prostate cancer develop CRPC within 5 years, and at least 84% of them have metastasized when CRPC is diagnosed. Of those men who did not metastasize when diagnosed with CRPC, 33% of patients may have metastases within 2 years. Although the treatment for this type of patient is increasing, their five-year survival rate is only 28%. There is still huge medical demand in this area that has not been met.

Lynparza is a PARP inhibitor and the first targeted therapy that has the potential to exploit DNA damage response (DDR) pathway defects (such as BRCA mutations) to preferentially kill cancer cells. In vitro studies have shown that Lyparza-induced cytotoxicity may involve inhibition of PARP enzyme activity, and increased formation of PARP-DNA complexes, leading to DNA damage and cancer cell death.

The study, Study 08, is a randomized, double-blind, multicenter, phase 2 clinical trial comparing Lynparza plus abiraterone combination therapy (n=71) with abiraterone monotherapy (n=71). Efficacy in treated mCRPC patients, regardless of the status of homologous recombination repair (HRR) mutations. The primary endpoint of the study was rPFS. Secondary endpoints included time to second progress or death (PFS2), overall survival (OS), and health-related quality of life.

The results showed that the median rPFS was 13.8 months in the Lynparza plus abiraterone combination therapy group and 8.2 months in the abiraterone monotherapy group (HR 0.65; 95% CI 0.44-0.97; p=0.034). The median PFS2 was 23.3 months and 18.5 months (HR 0.79; 95% CI 0.51-1.21). The median OS was 22.7 months and 20.9 months (HR 0.91; 95% CI 0.60-1.38). A pre-specified exploratory subgroup analysis showed that the patient's rPFS improved regardless of the HRR status. In addition, the safety of Lynparza plus abiraterone combination therapy is controllable, and there is no adverse effect on the quality of life of patients compared with abiraterone alone.

5. The total survival time is nearly 3 years! Pfizer announces potential new drug data for first-line lung cancer

Recently, Pfizer announced the overall survival (OS) data of its clinical trial ARCHER 1050. This study evaluated the efficacy of dacomitinib in the first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR activating mutations.

Lung cancer is the leading cause of cancer deaths worldwide, with NSCLC accounting for about 85% of lung cancer cases and still difficult to treat today. Approximately 75% of NSCLC patients are diagnosed at an advanced stage with a five-year survival rate of only 5%. EGFR is a growth factor receptor protein that helps cells grow and divide, and when it mutates, it can lead to cancer cell formation. EGFR mutations occur in 10% to 35% of NSCLC worldwide.

The dacomitinib brought by Pfizer belongs to the second generation EGFR TKI (tyrosine kinase inhibitor). Compared with the first generation of drugs, it is more effective in binding to EGFR, so it is expected to achieve more significant inhibition, thereby inhibiting tumor growth.

The published OS data is the second endpoint of ARCHER 1050, a randomized, open-label, phase 3 study comparing the efficacy and safety of dacomitinib and gefitinib in patients with locally advanced or metastatic NSCLC with EGFR activating mutations. Sex. The study showed that the median OS of the dacomitinib group was 34.1 months (95% CI: 29.5, 37.7), an improvement of more than 7 months compared to the control group of 26.8 months (95% CI: 23.7, 32.1). At 30 months, the survival rate was 56.2% in the dacomitinib group and 46.3% in the control group. Subgroup analyses were consistent with major OS analyses on most baseline characteristics, including patients with co-submutation exons 19 and 21. In addition, the adverse events (AEs) observed with dacomitinib observed in the study were consistent with the results of previous trials.

Reference materials:

[1] Genentech Announces FDA Approval for Venclexta Plus Rituxan for People With Previously Treated Chronic Lymphocytic Leukemia

[2] US FDA and European Medicines Agency Accept Regulatory Submissions for Review of Talazoparib for Metastatic Breast Cancer Patients with an Inherited BRCA Mutation

[3] Kite's TCR cell therapy offers promise for HPV-positive solid tumors

[4] Lynparza in combination with abiraterone delayed disease progression in metastatic castration-resistant prostate cancer

[5] Dacomitinib Shows More than Seven-Month Improvement in Overall Survival Compared to an Established Therapy in Advanced NSCLC with EGFR-Activating Mutations

Original Title: Summary of Recent Research Progress in the Field of Cancer (No. 69)

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