The DUBLIN-3 was a randomized phase III trial from BeyondSprings Pharmaceuticals in non-small cell lung cancer. It looked at an advanced non-small cell lung cancer, EGFR wild type. And I was looking at second and third-line treatment. Patients had to progress through at least one line of therapy, but two lines of progression were okay.
And patients had to have been exposed to platinum-based therapy. The randomized clinical trial was pretty broad in that it took patients with an ECOG performance status of 2 or better, and they had to have measurable disease in their lungs. Prior checkpoint inhibitor therapy was allowed. And the clinical trial testing superiority was re-randomized to the standard of care after the platinum failure of docetaxel at 75 milligrams per meter squared every 21 days plus or minus plinabulin, which was given at 30 milligrams per meter squared on days one and eight.
And at ESMO last year, we presented the survival data of DUBLIN-3. And here, we presented the primary endpoint, which was overall survival, showing that the addition of plinabulin improved overall survival from 9.4 months to 10.5 months. And we also saw an improvement in median overall survival. We saw an improvement in progression-free survival and a doubling of the overall response.
With the addition of plinabulin , we saw some reduction in toxicity. We saw a reduction in chemotherapy induced neutropenia. But is there an indication that might help in the prevention of chemotherapy induced neutropenia? We saw a slight increase in nausea and hypertension, and a slight increase in diarrhea. It was also interesting. We presented Q-TWiST, which was a measurement of time without symptoms for disease progression. Patient-reported outcomes for bone pain score and markers for immune suppression. Participants included patients receiving plinabulin, who had significantly less bone pain and a better immunosuppressive profile. Less bone pain can help study patients lead a better quality of life.
And we saw an 18% improvement in Q-TWiST. This year at ASCO, we presented two abstracts, but specifically, I'm going to focus more on 9091, which looked at quality of life measurements. Herein, we showed that there was no change in the quality of life for the first 10 cycles of treatment. However, after 10 cycles, we saw the additional plinabulin become more favorable, and after 20 cycles, it significantly improved the quality of life with the additional plinabulin.
It should be noted that not all patients received this many cycles of treatment, but cycles were continued until disease progression. What we saw, specifically looking at the quality of life, is that patients receiving plinabulin had fewer coughs, less dysphasia, and fewer sore throats.
We saw a slightly increased risk of hemostasis, which we'll get into in a little bit. What I also found very interesting is cancer patients randomized to plinabulin did receive more cycles of docetaxel, and neuropathy was not worse with the addition of plinabulin , which was interesting to see that patients getting more cycles of docetaxel did not have worse neuro.
So, what this really supports is that the additional plinabulin one is well tolerated and probably helps reduce some of the toxicity of chemo, resulting in fewer clinical consequences.
In regards to that, the most common question I get is: what is plinabulin? Plurabulin is a novel immune-enhancing small molecule. Felt to bind to the Microtus, and through this, it induces dendritic cell maturation, activating the immune system through FH1, but also it has some VEGF properties, which is why we saw that there was probably a slightly increased risk of hemostasis.
No, this data won't affect clinicians today as plinabulin is not an approved agent. So, as of today, it does not change things, but it's interesting to let people know that there are nice combinations coming out with docetaxel that might help with some of the toxicity of chemotherapy dose.
The next step? The first research is to probably combine plinabulin with other agents that are being studied in other cancers. As we've seen, it's well tolerated and does help reduce some of the toxicity of the chemotherapy cycle. So right now, we're looking at other combinations where it falls out in lung cancer. I'm not quite certain.
It might. I think it needs some testing, maybe in first-line combined with checkpoint inhibitors, given its immune activity. But it's still got some further testing to go through before approval.
What I think would be nice just to highlight is that our abstract next to it was 90, 90. And here, we looked at non-squamous lung cancer. And here, what we saw is that there was a further improvement in overall survival. We realize it's a subgroup analysis, but that overall survival improved with additional plinabulin from 8.8 months to 11.4 months.
And what we think is that survival is greater in non-squamous histology. Because in the squamous we saw the HESIs, which occurred, we probably deduced some of the overall survival. And about a third of patients did have squama histology on the Dublin-3.
Because of his significant experience in oncology and hematology, Dr. Trevor Feinstein treats patients with all cancer types. He holds diplomate status with the American Boards of Hematology and Oncology. In 2011, he joined Piedmont Cancer Institute. Prior to joining PCI, he worked in private practice in West Palm Beach, Florida, treating cancer patients.
Dr. Feinstein has received various honors and awards, including the Thomas O'Toole Award for exceptional work with underprivileged people, a Sanofi-Aventis Grant, and the Amgen Fellowship Award. He helped bring the DigniCap Scalp Cooling System to Piedmont Cancer Institute. PCI was the first facility in Georgia to offer DigniCap, which minimizes the risk of chemotherapy-induced baldness (hair loss).
Dr. Feinstein has published more than 30 peer-reviewed papers, abstracts, and manuscripts in the fields of hematology and oncology. He has provided international talks on lung cancer treatment, including a paper presented at the ESMO (European Society of Medical Oncology) and leading the AstraZenca Lung Cancer Summit in Beijing. He is the co-director of Piedmont Cancer's research department. He is the director of research at Piedmont Fayette Hospital and a member of Piedmont Hospital's Oncology Scientific Review Committee.
In this video, he speaks about the ASCO 2022 Abstract - DUBLIN-3 results on quality of life (QoL) in second/third-line EGFR-wild type non-small cell lung cancer (NSCLC) patients (pts) receiving docetaxel (Doc) with or without plinabulin using the validated EORTC QLQ C30 and QLQ LC13 questionnaires.
Lung cancer is the leading cause of cancer-related death worldwide. According to the World Health Organization's Global Cancer Observatory, there will be 2.09 million new cases and 1.76 million deaths worldwide in 2018. (GLOBOCAN, 2018, Fact Sheet N039). With an estimated 774,323 new cases and 690,567 deaths in 2018, China has a comparatively high incidence and mortality rate for lung cancer (GLOBOCAN, 2018, Fact Sheet N0160 China). According to the National Cancer Institute, in the United States in 2020, there will be approximately 228,820 new cases and 135,720 deaths from lung cancer, accounting for approximately 22.4 percent of all cancer deaths (SEER program, 2020). Non-small cell lung cancer (NSCLC) accounts for around 84 percent of all lung malignancies in the United States (American Cancer Society, 2020).
Plurabulin, BeyondSpring Pharmaceuticals' first-in-class lead asset, is being developed as a "pipeline in a medication" in many cancer indications as a direct anti-cancer agent and to avoid chemotherapy induced neutropenia (CIN). The combination of plinabulin and G-CSF for the prevention of CIN has shown promising Phase 3 results. The plinabulin and docetaxel combination met the primary aim of extending overall survival relative to docetaxel alone in the DUBLIN-3 study, a global, randomized, active-controlled Phase 3 trial in 2nd and 3rd line NSCLC (EGFR wild type). Furthermore, plinabulin is being examined extensively in conjunction with several immuno-oncology regimens that may improve the efficacy of PD-1/PD-L1 antibodies in seven distinct malignancies. BeyondSpring's pipeline also includes three pre-clinical immuno-oncology assets and a subsidiary, SEED Therapeutics, which is developing drugs using a patented targeted protein degradation drug discovery technology.
Patients with advanced or metastatic NSCLC have a terrible prognosis, whether it is their initial diagnosis or a recurrence. The standard of care has been chemotherapy with platinum analogs, taxanes, vinca alkaloids, and pemetrexed in combination 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.
For patients who do not have a clear molecular target, first-line therapy is usually a programmed cell death protein 1 (PD-1) inhibitor or a platinum-containing double agent combination. Platinum comes in two forms: cisplatin and carboplatin, and the most commonly used drugs in combination with platinum are paclitaxel, docetaxel, gemcitabine, and vinorelbine, as well as irinotecan, etoposide, and vinblastine.
The introduction of immunotherapy with the PD-1 inhibitor pembrolizumab changed the first-line standard dramatically. Pembrolizumab has a long duration of response (DoR), but response rates remain low (about 45 percent in first-line [Keytruda® Prescribing Information. 2020]). When patients with NSCLC fail to respond to or become refractory to targeted or immune-based therapies, docetaxel remains a potential treatment option.
Platinum-free double-agent chemotherapy regimens are used for patients who are intolerant to platinum-containing regimens. For patients with an Eastern Cooperative Oncology Group score of 2 and the elderly, single-agent or double-agent regimens are recommended. A single medication, Gefitinib, has been approved in China for the first-line treatment of patients with locally advanced or metastatic NSCLC who have an EGFR tyrosine kinase sensitivity mutation.
Docetaxel, pemetrexed, EGFR-tyrosine kinase inhibitor (TKI) for EGFR mutant patients, and checkpoint inhibitors are examples of second-line treatment medications (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, but efficacy, as measured by clinical improvement or overall survival, has been limited (OS). EGFR wild type accounts for roughly 85% of the western NSCLC population and 70% of the Asian NSCLC population. Checkpoint inhibition using PD1/programmed death-ligand 1 (PD-L1) inhibitors in combination with chemotherapy agents or other checkpoint inhibitors has moved into first-line treatment and is gradually being phased out of second- or third-line treatment. Docetaxel-based regimens have thus become the standard of care in 2nd and 3rd-line NSCLC. As a result, the comparison of plinabulin with docetaxel against docetaxel alone has grown in significance.
Docetaxel, a taxane, binds to and stabilizes tubulin, limiting microtubule disintegration and, as a result, G2/M cell cycle arrest and cell death. In patients with NSCLC who had previously had a platinum-based chemotherapy cycle, second-line docetaxel treatment provided a median OS of 5.7 to 7.5 months (Fossella, 2000; Shepherd, 2000). The most common adverse events (AEs) were infections, neutropenia (to help prevent chemotherapy induced 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 (Taxotere Prescribing Information, 2020). (If these toxicities persist, permanent chemotherapy discontinuation or a chemotherapy dose delay is recommended and has fewer adverse clinical consequences.) Since the approval of docetaxel in 1999 as a second-line treatment for advanced or metastatic NSCLC, two other drugs, pemetrexed, and erlotinib, have been approved for the same indication. Nonetheless, despite the availability of newer medications, patient survival with docetaxel has not improved. In these clinical trials, the OS ranged between 5.6 and 8.3 months (Hanna et al., 2004; Kim et al., 2008; Shepherd et al., 2005), in these patient-reported outcomes.
According to a retrospective evaluation of the plinabulin Phase 2 investigation, Plinabulin improves survival in NSCLC patients with identifiable lung tumors. Patients with identifiable lung lesions are expected to have immunogenic antigens capable of activating the immune system. Patients receiving docetaxel therapy are expected to unleash these immunogens, whereas patients receiving plinabulin are likely to increase their presentation to the T-cell repertoire via dendritic cell activation.
The goal of this plinabulin clinical trial is to investigate the clinical outcomes of the efficacy and safety of combining plinabulin with docetaxel in patients with EGFR wild-type NSCLC and advanced malignancies who require second-or third-line therapy for advanced or metastatic cancer after failing a platinum-containing regimen. Overall survival is the primary outcome, with docetaxel monotherapy serving as an active comparator. In reducing chemotherapy induced neutropenia.
BeyondSpring Pharmaceuticals, a global pharmaceutical company focused on cancer therapeutic development, announced today that it has received a Complete Response Letter (CRL) from the U.S. Food and Drug Administration (FDA) for the New Drug Application (NDA) seeking approval of plinabulin in combination with granulocyte colony-stimulating factor (G-CSF) for the prevention of chemotherapy induced neutropenia (CIN). The FDA issued the CRL to signal that they had finished reviewing the application and found that it could not be approved in its current form. According to the FDA's CRL, the results of the sole registrational trial (106 Phase 3) were not sufficiently robust to establish benefit, and a second well-controlled trial would be necessary to satisfy the substantial evidence criteria to support the chemotherapy induced neutropenia (CIN) indication.
Currently, there is no FDA approved therapy for the prevention of CIN, and plinabulin is the first drug candidate submitted to the FDA for its potential to prevent CIN in patients. The research on plinabulin is ongoing with the goal of reaching its primary endpoint.
BeyondSpring's lead asset, plinabulin, is a selective immunomodulating microtubule-binding agent (SIMBA) that induces antigen-presenting cells (APCs). It is an intravenous infused, patent-protected, NDA-stage asset for CIN prevention as well as a Phase 3 anti-cancer candidate for non-small cell lung cancer (NSCLC) with recently revealed favorable topline data. Plinabulin causes the immune defense protein GEF-H1 to be released, which has two distinct effects: the first is a long-term anticancer benefit due to dendritic cell maturation, which results in the activation of tumor antigen-specific T-cells to target cancer cells, and the second is an early onset of action in CIN prevention after chemotherapy by increasing the number of hematopoietic stem/progenitor cells (HSPCs). For the CIN prevention indication, BeyondSpring Pharmaceuticals' Plinabulin obtained Breakthrough Therapy designation and priority evaluation from both the US and Chinese FDAs for the CIN prevention indication. Plinabulin is being explored extensively as a "pipeline in a medication" in combination with several immuno-oncology drugs to increase the effects of PD-1/PD-L1 antibodies and re-sensitize PD-1/PD-L1 antibody-resistant patients.
BeyondSpring Pharmaceuticals - BeyondSpring Pharmaceuticals Receives Complete Response Letter From The FDA For Plinabulin New Drug Application For Prevention Of Chemotherapy Induced Neutropenia (CIN). BeyondSprings News, December 1, 2021
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