Podcast Trevor M. Feinstein, MD #PiedmontCancerInstitute #ASCO22 #OncoTwitter @oncoalert DUBLIN-3 Phase III Study

Podcast Trevor M. Feinstein, MD #PiedmontCancerInstitute ...

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Trevor M. Feinstein, MD, Oncologist, Hematologist at Piedmont Cancer Institute. In this audio, he speaks about the ASCO 2022 Abstract - DUBLIN-3 results on quality of life (QoL) in second/third-line EGFR-wild type NSCLC patients (pts) receiving docetaxel (Doc) with or without plinabulin (Plin) using the validated EORTC QLQ C30 and QLQ LC13 questionnaires. 

Synopsis:

Lung cancer is the biggest cause of cancer-related death globally. In 2018, there were a projected 2.09 million new cases and 1.76 million deaths worldwide, according to the World Health Organization's Global Cancer Observatory (GLOBOCAN, 2018, Fact Sheet N039). China has a relatively high incidence and mortality rate for lung cancer, with an expected 774,323 new cases and 690,567 deaths in 2018 (GLOBOCAN, 2018, Fact Sheet N0160 China). According to the National Cancer Institute, there will be approximately 228,820 new cases and 135,720 deaths from lung cancer in the United States in 2020, accounting for approximately 22.4 percent of all cancer deaths (SEER program, 2020). In the United States, NSCLCs account for around 84 percent of all lung cancers (American Cancer Society, 2020).

Patients with advanced or metastatic NSCLC, whether at first diagnosis or recurrence, have a poor prognosis. Chemotherapy with platinum analogs, taxanes, vinca alkaloids, and pemetrexed with vascular endothelial growth factor inhibitors and, for patients with appropriate disease genotypes, epidermal growth factor receptor (EGFR) inhibitors or anaplastic lymphoma kinase (ALK) inhibitors has been the standard of care.

First-line therapy is commonly a programmed cell death protein 1 (PD-1) inhibitor or a platinum-containing, double agent combination for patients who do not have a clear molecular target. Platinum can be cisplatin or carboplatin, and the most widely used medications in combination with platinum include paclitaxel, docetaxel, gemcitabine, and vinorelbine, as well as irinotecan, etoposide, and vinblastine.

The introduction of immunotherapy with the PD-1 inhibitor pembrolizumab significantly altered the first-line standard. Pembrolizumab is highly successful, with a lengthy Duration of Response (DoR), but response rates remain low (about 45 percent in first-line [Keytruda® Prescribing Information. 2020]). Most patients will eventually fail first-line therapy, and docetaxel remains a viable treatment choice when NSCLC patients fail to react to or become refractory to targeted or immune-based therapies.

Platinum-free double-agent chemotherapy regimens are utilized as an alternative for individuals who are intolerant to platinum-containing regimens. Single-agent or double-agent regimens are advised for patients with an Eastern Cooperative Oncology Group score of 2 and the elderly. Gefitinib, a single drug, has been approved in China for the first-line treatment of patients with locally progressed or metastatic NSCLC who have a sensitivity mutation in the EGFR tyrosine kinase gene.

Second-line therapy drugs include docetaxel, pemetrexed, EGFR-tyrosine kinase inhibitor (TKI) for EGFR mutant patients, and checkpoint inhibitors (such as nivolumab and pembrolizumab).

Several second-line treatment drugs and regimens (docetaxel, pemetrexed, and ramucirumab in combination with docetaxel) have been approved as single agents or in combination for second-line therapy for locally advanced or metastatic NSCLC with EGFR wild type with limited efficacy, as measured by clinical improvement or overall survival (OS). EGFR wild type accounts for approximately 85 percent of the western NSCLC population and approximately 70 percent of the Asian NSCLC population. Checkpoint inhibition using PD 1/programmed death-ligand 1 (PD-L1) inhibitors in combination with chemotherapy or other checkpoint inhibitors has moved into first line and is progressively being excluded from 2nd/3rd line treatment. As a result, docetaxel-based regimens have become standard-of-care in 2nd/3rd line NSCLC. As a result, the comparison of plinabulin with docetaxel against docetaxel alone has become quite important.

Docetaxel, a taxane, binds to and stabilizes tubulin, preventing microtubule disintegration and, as a result, cell cycle arrest during the G2/M phase and cell death. Second-line docetaxel therapy provided a median OS of 5.7 to 7.5 months in patients with NSCLC who had previously received platinum-based chemotherapy (Fossella, 2000; Shepherd, 2000). Infections, neutropenia, anemia, febrile neutropenia (FN), hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, and myalgia were the most common adverse events (AEs) (Taxotere Prescribing Information, 2020). Since the introduction of docetaxel as a second-line treatment for advanced or metastatic NSCLC in 1999, two more medicines, pemetrexed and erlotinib, have been licensed for the same indication. Nonetheless, despite the availability of newer medicines, patient survival has not improved with docetaxel. The OS in these trials was found to be between 5.6 and 8.3 months (Hanna et al., 2004; Kim et al., 2008; Shepherd et al., 2005).

According to a retrospective review of the plinabulin Phase 2 research, plinabulin improves survival in NSCLC patients with detectable lung tumors. The expectation is that patients with detectable lung lesions may still have immunogenic antigens capable of triggering the immune system. Docetaxel therapy is expected to release these immunogens, and plinabulin is expected to improve presentation of these immunogens to the T-cell repertoire via dendritic cell activation.

The purpose of this plinabulin trial is to look into the efficacy and safety of combining plinabulin with docetaxel in patients with EGFR wild type NSCLC and advancing tumors who need second- or third-line therapy for advanced or metastatic cancer after failing a platinum-containing regimen. The primary outcome is overall survival, with docetaxel monotherapy serving as an active comparator.