On April 17, 2020 Seattle Genetics, Inc. (Nasdaq:SGEN) reported the U.S. Food and Drug Administration (FDA) granted approval to TUKYSA (tucatinib) tablets in combination with trastuzumab and capecitabine for adult patients with advanced unresectable (cannot be surgically removed) or metastatic HER2-positive breast cancer, including patients with brain metastases (disease that has spread to the brain), who have received one or more prior anti-HER2-based regimens in the metastatic setting (Press release, Seattle Genetics, APR 17, 2020, View Source [SID1234556408]). The FDA previously granted Breakthrough Therapy designation and Priority Review for TUKYSA and reviewed this application for approval under the Real-Time Oncology Review (RTOR) pilot program. The TUKYSA New Drug Application (NDA) is also part of Project Orbis, an initiative of the FDA Oncology Center of Excellence that provides a framework for concurrent submission and review of oncology drugs among participating international health authorities. TUKYSA is an oral, small molecule tyrosine kinase inhibitor (TKI) of HER2, a protein that contributes to cancer cell growth.1,2

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(Photo: Business Wire)
(Photo: Business Wire)

"With highly significant and clinically important results for overall and progression-free survival, the addition of TUKYSA to trastuzumab and capecitabine has the potential to become a standard of care for people with HER2-positive metastatic breast cancer after having received one or more previous anti-HER2 therapies in the metastatic setting," said Eric P. Winer, MD, Chief of the Division of Breast Oncology, Susan F. Smith Center for Women’s Cancers at Dana-Farber. "Cancer spreads to the brain in up to half of patients with HER2-positive metastatic breast cancer; and this approval is based on a unique clinical trial that included patients with active brain metastases, either untreated or progressing. TUKYSA is well tolerated by patients and is a valuable addition to the agents we have for HER2-positive metastatic breast cancer."

"We’re pleased to have collaborated with the FDA on our second expedited real-time oncology review, enabling us to rapidly bring this new targeted medicine to patients," said Clay Siegall, Ph.D., Chief Executive Officer at Seattle Genetics. "TUKYSA has shown impressive results in people with HER2-positive metastatic breast cancer, including in patients with active brain metastases, and offers patients an effective medicine following previous treatment with other anti-HER2 agents in the metastatic setting."

TUKYSA, in combination with trastuzumab and capecitabine, was evaluated in the trial HER2CLIMB, a randomized (2:1), double-blind, placebo-controlled trial that enrolled 612 patients with HER2-positive unresectable locally advanced or metastatic breast cancer who had previously received, either separately or in combination, trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-DM1). Forty-eight percent of patients in the study had a presence or history of brain metastases. The primary efficacy outcome measure was progression-free survival (PFS) as assessed by blinded independent central review (BICR) in the first 480 randomized patients.1 Additional efficacy outcome measures were evaluated in all randomized patients and included overall survival (OS), PFS in patients with a history or presence of brain metastases, and confirmed objective response rate (ORR).

Patients who received TUKYSA in combination with trastuzumab and capecitabine had a 46 percent reduction in the risk of cancer progression or death (PFS) compared to patients who received trastuzumab and capecitabine alone (hazard ratio (HR)=0.54 [95% Confidence Interval (CI): 0.42, 0.71]; p<0.00001). The addition of TUKYSA reduced the risk of death (OS) by 34 percent compared to trastuzumab and capecitabine alone (HR=0.66 [95% CI: 0.50, 0.87]; p=0.0048). Nearly twice the number of patients who received TUKYSA in combination with trastuzumab and capecitabine had a confirmed objective response compared to those who received trastuzumab and capecitabine alone (40.6 percent (95% CI: 35.3, 46.0) vs. 22.8 percent (95% CI: 16.7, 29.8); p=0.00008). For patients with brain metastases, the addition of TUKYSA reduced the risk of cancer progression or death (PFS) by 52 percent compared to trastuzumab and capecitabine alone (HR=0.48 [95% CI: 0.34, 0.69]; p<0.00001).

Serious adverse reactions occurred in 26 percent of patients who received TUKYSA. Serious adverse reactions occurring in 2 percent or more of patients who received TUKYSA were diarrhea (4%), vomiting (2.5%), nausea, abdominal pain, and seizure (2% each). The most common adverse reactions occurring in 20 percent or more of patients who received TUKYSA were diarrhea, palmar-plantar erythrodysesthesia, nausea, fatigue, hepatotoxicity, vomiting, stomatitis, decreased appetite, abdominal pain, headache, anemia, and rash. Adverse reactions leading to treatment discontinuation occurred in 6 percent of patients who received TUKYSA; adverse reactions leading to treatment discontinuation of TUKYSA (in 1 percent or more of patients) were hepatotoxicity (1.5%) and diarrhea (1%).

The data were published in The New England Journal of Medicinein December 2019.

About TUKYSA (tucatinib)

TUKYSA is an oral medicine that is a tyrosine kinase inhibitor of the HER2 protein. In vitro (in lab studies), TUKYSA inhibited phosphorylation of HER2 and HER3, resulting in inhibition of downstream MAPK and AKT signaling and cell growth (proliferation), and showed anti-tumor activity in HER2-expressing tumor cells. In vivo (in living organisms), TUKYSA inhibited the growth of HER2-expressing tumors. The combination of TUKYSA and the anti-HER2 antibody trastuzumab showed increased anti-tumor activity in vitro and in vivo compared to either medicine alone.1

SeaGen Secure offers access and reimbursement support to help patients access TUKYSA. For more information, go to SeaGenSecure.com.

About HER2-Positive Breast Cancer

Patients with HER2-positive breast cancer have tumors with high levels of a protein called human epidermal growth factor receptor 2 (HER2), which promotes the growth of cancer cells. An estimated 279,100 new cases of breast cancer will be diagnosed in the U.S. in 2020.3 Between 15 and 20 percent of breast cancer cases are HER2-positive.3 Historically, HER2-positive breast cancer tends to be more aggressive and more likely to recur than HER2-negative breast cancer.4,5,6 Up to 50 percent of metastatic HER2-positive breast cancer patients develop brain metastases over time.7,8,9

Important Safety Information

Warnings and Precautions

Diarrhea – TUKYSA can cause severe diarrhea including dehydration, hypotension, acute kidney injury, and death. In HER2CLIMB, 81% of patients who received TUKYSA experienced diarrhea, including 12% with Grade 3 diarrhea and 0.5% with Grade 4 diarrhea. Both patients who developed Grade 4 diarrhea subsequently died, with diarrhea as a contributor to death. The median time to onset of the first episode of diarrhea was 12 days and the median time to resolution was 8 days. Diarrhea led to dose reductions of TUKYSA in 6% of patients and discontinuation of TUKYSA in 1% of patients. Prophylactic use of antidiarrheal treatment was not required on HER2CLIMB.

If diarrhea occurs, administer antidiarrheal treatment as clinically indicated. Perform diagnostic tests as clinically indicated to exclude other causes of diarrhea. Based on the severity of the diarrhea, interrupt dose, then dose reduce or permanently discontinue TUKYSA.
Hepatotoxicity – TUKYSA can cause severe hepatotoxicity. In HER2CLIMB, 8% of patients who received TUKYSA had an ALT increase >5 × ULN, 5% had an AST increase >5 × ULN, and 1.5% had a bilirubin increase >3 × ULN (Grade ≥3). Hepatotoxicity led to dose reduction of TUKYSA in 8% of patients and discontinuation of TUKYSA in 1.5% of patients.

Monitor ALT, AST, and bilirubin prior to starting TUKYSA, every 3 weeks during treatment, and as clinically indicated. Based on the severity of hepatoxicity, interrupt dose, then dose reduce or permanently discontinue TUKYSA.
Embryo-Fetal Toxicity – TUKYSA can cause fetal harm. Advise pregnant women and females of reproductive potential risk to a fetus. Advise females of reproductive potential, and male patients with female partners of reproductive potential, to use effective contraception during TUKYSA treatment and for at least 1 week after the last dose.
Adverse Reactions

Serious adverse reactions occurred in 26% of patients who received TUKYSA. Serious adverse reactions in ≥2% of patients who received TUKYSA were diarrhea (4%), vomiting (2.5%), nausea (2%), abdominal pain (2%), and seizure (2%). Fatal adverse reactions occurred in 2% of patients who received TUKYSA including sudden death, sepsis, dehydration, and cardiogenic shock.

Adverse reactions led to treatment discontinuation in 6% of patients who received TUKYSA; those occurring in ≥1% of patients were hepatotoxicity (1.5%) and diarrhea (1%). Adverse reactions led to dose reduction in 21% of patients who received TUKYSA; those occurring in ≥2% of patients were hepatotoxicity (8%) and diarrhea (6%).

The most common adverse reactions in patients who received TUKYSA (≥20%) were diarrhea, palmar-plantar erythrodysesthesia, nausea, fatigue, hepatotoxicity, vomiting, stomatitis, decreased appetite, abdominal pain, headache, anemia, and rash.

Lab Abnormalities

In HER2CLIMB, Grade ≥3 laboratory abnormalities reported in ≥5% of patients who received TUKYSA were: decreased phosphate, increased ALT, decreased potassium, and increased AST. The mean increase in serum creatinine was 32% within the first 21 days of treatment with TUKYSA. The serum creatinine increases persisted throughout treatment and were reversible upon treatment completion. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed.

Drug Interactions

Strong CYP3A or Moderate CYP2C8 Inducers: Concomitant use may decrease TUKYSA activity. Avoid concomitant use of TUKYSA.
Strong or Moderate CYP2C8 Inhibitors: Concomitant use of TUKYSA with a strong CYP2C8 inhibitor may increase the risk of TUKYSA toxicity; avoid concomitant use. Increase monitoring for TUKYSA toxicity with moderate CYP2C8 inhibitors.
CYP3A Substrates: Concomitant use may increase the toxicity associated with a CYP3A substrate. Avoid concomitant use of TUKYSA where minimal concentration changes may lead to serious or life-threatening toxicities. If concomitant use is unavoidable, decrease the CYP3A substrate dosage.
P-gp Substrates: Concomitant use may increase the toxicity associated with a P-gp substrate. Consider reducing the dosage of P-gp substrates where minimal concentration changes may lead to serious or life-threatening toxicity.
Use in Specific Populations

Lactation: Advise women not to breastfeed while taking TUKYSA and for at least 1 week after the last dose.
Renal Impairment: Use of TUKYSA in combination with capecitabine and trastuzumab is not recommended in patients with severe renal impairment (CLcr < 30 mL/min), because capecitabine is contraindicated in patients with severe renal impairment.
Hepatic Impairment: Reduce the dose of TUKYSA for patients with severe (Child-Pugh C) hepatic impairment.
For more information, please see the full Prescribing Information for TUKYSA here.

Conference Call Details

Seattle Genetics’ management will host a conference call and webcast to discuss the approval of TUKYSA today at 1:00 p.m. Pacific Time (PT); 4:00 p.m. Eastern Time (ET). The live event will be simultaneously webcast and available for replay from the Seattle Genetics website at www.seattlegenetics.com, under the Investors section. Investors may also participate in the conference call by calling 888-220-8451 (domestic) or 323-794-2588 (international). The conference ID is 5796578. A replay of the audio only will be available by calling 888-203-1112 (domestic) or 719-457-0820 (international), using conference ID 5796578. The telephone replay will be available until 5:00 p.m. PT on April 20, 2020.

On April 17, 2020 Hutchison China MediTech Limited ("Chi-Med") (Nasdaq/AIM: HCM) reported that the U.S. Food and Drug Administration ("FDA") has granted two Fast Track Designations for the development of surufatinib, for the treatment of both advanced and progressive pancreatic neuroendocrine tumors ("NET") and extra-pancreatic (non-pancreatic) NET in patients who are not amenable for surgery (Press release, Hutchison China MediTech, APR 17, 2020, https://www.chi-med.com/surufatinib-granted-us-fda-fast-track-designations/ [SID1234556402]).

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The FDA Fast Track Designation is one of several approaches utilized by the U.S. FDA to expedite development and review of potential medicines for serious conditions and that fulfill unmet medical needs. A potential new medicine may fill an unmet medical need by being the first therapy to address a specific serious condition, offer clinically significant advantages over available therapies, act via a different mechanism of action than available therapies, or have a benefit in patients who are unresponsive to or intolerant of available therapies. Programs that receive Fast Track Designation are entitled to more frequent interactions with the U.S. FDA on drug development plan, as well as eligibility for accelerated approval, priority review, and rolling review.[1]

About Surufatinib
Surufatinib is a novel, oral angio-immuno kinase inhibitor that selectively inhibits the tyrosine kinase activity associated with vascular endothelial growth factor receptor ("VEGFR") and fibroblast growth factor receptor (FGFR), which both inhibit angiogenesis, and colony stimulating factor-1 receptor (CSF-1R), which regulates tumor-associated macrophages, promoting the body’s immune response against tumor cells. Its unique dual mechanism of action may be very suitable for possible combinations with other immunotherapies.

Chi-Med currently retains all rights to surufatinib worldwide.

Neuroendocrine tumors in the U.S., Europe and Japan: We are preparing for regulatory interactions in the U.S., Europe and Japan to confirm clinical development and path to registration, based on the encouraging data from the two positive Phase III studies of surufatinib in NET in China, and the ongoing multi-cohort Phase Ib study in the U.S. (clinicaltrials.gov identifier: NCT02549937). In addition to the aforementioned grants of Fast Track Designation in pancreatic and non-pancreatic NET in the U.S., surufatinib was granted Orphan Drug Designation for pancreatic NET in November 2019.

Non-pancreatic neuroendocrine tumors in China: In November 2019, an NDA for surufatinib for the treatment of patients with advanced extra-pancreatic (non-pancreatic) neuroendocrine tumors was accepted for review by the China NMPA and granted Priority Review status in December 2019. The NDA is supported by data from the successful SANET-ep study, a Phase III study of surufatinib in advanced neuroendocrine tumors – extra-pancreatic patients in China for whom there is no effective therapy. A 198-patient interim analysis was conducted in June 2019, leading the Independent Data Monitoring Committee ("IDMC") to determine that the study met the pre-defined primary endpoint of progression-free survival ("PFS") and should be stopped early. The positive results of this trial were highlighted in an oral presentation at the 2019 European Society for Medical Oncology Congress (clinicaltrials.gov identifier: NCT02588170).

Pancreatic neuroendocrine tumors in China: In 2016, we initiated the SANET-p study, which is a pivotal Phase III study in patients with low- or intermediate-grade, advanced pancreatic NET in China. A second NDA for surufatinib for the treatment of patients with advanced pancreatic NET is being prepared for submission, following an interim analysis review conducted in January 2020 by the IDMC that recommended that registrational study be terminated early as the pre-defined primary endpoint of PFS had already been met (clinicaltrials.gov identifier: NCT02589821). Study results will be submitted for presentation at an upcoming scientific conference.

Biliary tract cancer in China: In March 2019, we initiated a Phase IIb/III study comparing surufatinib with capecitabine in patients with advanced biliary tract cancer whose disease progressed on first-line chemotherapy. The primary endpoint is overall survival (OS) (clinicaltrials.gov identifier NCT03873532).

Immunotherapy combinations: In November 2018 and September 2019, we entered into collaboration agreements to evaluate the safety, tolerability and efficacy of surufatinib in combination with anti-programmed cell death protein 1 (PD-1) monoclonal antibodies. This included global collaborations to evaluate the combination of surufatinib with Tuoyi, approved in China by Shanghai Junshi Biosciences Co. Ltd, and with Tyvyt, approved in China by Innovent Biologics, Inc.

About Neuroendocrine Tumors (NET)
Neuroendocrine tumors form in cells that interact with the nervous system or in glands that produce hormones. They can originate in various parts of the body, most often in the gut or the lungs and can be benign or malignant. Neuroendocrine tumors are typically classified as pancreatic neuroendocrine tumors or non-pancreatic neuroendocrine tumors. Approved targeted therapies include Sutent and Afinitor for pancreatic neuroendocrine tumors, or well-differentiated, non-functional gastrointestinal or lung neuroendocrine tumors.

According to Frost and Sullivan, there were 19,000 newly diagnosed cases of neuroendocrine tumors in the U.S. in 2018. Importantly, neuroendocrine tumors are associated with a relatively long duration of survival compared to other tumors. As a result, there were approximately 141,000 estimated patients living with neuroendocrine tumors in the U.S. in 2018 of which over 90%, or approximately 132,000, were non-pancreatic neuroendocrine tumor patients.

In China, there were approximately 67,600 newly diagnosed neuroendocrine tumor patients in 2018 and, considering the current incidence to prevalence ratio in China, potentially as many as 300,000 patients living with the disease in the country[2]. It is estimated that approximately 80% of the patients living with neuroendocrine tumors in China are non-pancreatic neuroendocrine tumor patients.

On April 16, 2020 Turning Point Therapeutics, Inc. (NASDAQ: TPTX), a precision oncology company developing next-generation therapies that target genetic drivers of cancer, reported the publication of preclinical data and patient case studies from the Phase 1 portion of its TRIDENT-1 clinical study for its lead investigational drug, repotrectinib (Press release, Turning Point Therapeutics, APR 16, 2020, View Source [SID1234564376]).

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Among the findings published in the American Association of Cancer Research peer-reviewed journal, Clinical Cancer Research, repotrectinib demonstrated potent in vitro and in vivo activity in patient-derived preclinical models compared with proxy chemical compounds for other tyrosine kinase inhibitors (TKIs) against ROS1 and the ROS1 G2032R solvent-front mutation. The central nervous system (CNS) activity of repotrectinib was studied in an in vivo model and demonstrated significant reduction of metastatic brain lesions with longer survival compared to a proxy chemical compound for entrectinib.

"Our findings provide encouraging support for repotrectinib as a potential first-line treatment in ROS1-positive non-small cell lung cancer, and later-line use after progression from a prior ROS1 TKI," said Dr. Byoung Chul Cho, Division of Medical Oncology, Yonsei Cancer Center at Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea and corresponding author of the paper. "In addition, these preclinical data as presented initially at the annual AACR (Free AACR Whitepaper) conference in 2019 and now expanded upon in the publication suggest repotrectinib may prevent or delay the emergence of the G2032R solvent-front mutation and subsequent compound mutations, potentially improving clinical outcomes."

In preclinical studies, repotrectinib potently inhibited in vitro and in vivo tumor growth and ROS1-downstream signaling in treatment-naïve models compared with proxy chemical compounds for crizotinib, ceritinib, and entrectinib. Compared to a lorlatinib proxy chemical compound in a xenograft model, repotrectinib markedly delayed the onset of tumor recurrence following drug withdrawal. In addition, repotrectinib induced anti-tumor activity in the CNS. Repotrectinib also showed selective and potent in vitro and in vivo activity against the ROS1 G2032R solvent-front mutation.

Patient case studies (from the previously reported July 22, 2019 data cut-off) included in the manuscript highlighted the potential for repotrectinib to prevent or delay ROS1 kinase domain resistance mutations.

"The emergence of resistance mutations and disease progression in the CNS are characteristics of ROS1-positive non-small cell lung cancer and represent a high unmet medical need given the lack of approved therapies," said Dr. Mohammad Hirmand, chief medical officer of Turning Point Therapeutics. "These findings highlighted in Clinical Cancer Research build on prior preclinical studies of repotrectinib and data we have shown from the Phase 1 portion of TRIDENT-1, and are encouraging for repotrectinib as a potential treatment for both TKI-naïve and -pretreated ROS1-positive non-small cell lung cancer patients."

Approximately 50 to 60 percent of crizotinib-resistant mutations are found within the ROS1 kinase, of which the ROS1 G2032R solvent-front mutation is the most common. In addition, it is estimated that approximately 50 percent of patients treated with ROS1-TKIs experience disease progression due to CNS metastases.

The Clinical Cancer Research article may be found online at View Source

More information about the ongoing TRIDENT-1 study of repotrectinib may be found by searching clinical trial identifier NCT03093116 at View Source

On April 16, 2020 Foundation Medicine, Inc. reported that the U.S. Food and Drug Administration (FDA) approved FoundationOneCDx as the registrational companion diagnostic for Incyte’s Pemazyre (pemigatinib), a selective fibroblast growth factor receptor (FGFR) inhibitor approved for adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by an FDA-approved test (Press release, Foundation Medicine, APR 16, 2020, View Source [SID1234556420]). FoundationOne CDx is the first and only FDA-approved companion diagnostic test for this indication.

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Cholangiocarcinoma is a rare cancer, diagnosed in approximately 8,000 patients annually, according to the American Cancer Society. It is classified based on its origin: intrahepatic cholangiocarcinoma (iCCA) occurs in the bile duct inside the liver and extrahepatic cholangiocarcinoma occurs in the bile duct outside the liver. FGFR2 fusions or select rearrangements occur in 10-16 percent of iCCA patients.1, 2, 3 Because this cancer is difficult to detect, patients with cholangiocarcinoma are often diagnosed at a late or advanced stage when the prognosis is poor and treatment options are limited.4 The approval of this novel therapy and companion diagnostic means healthcare professionals will be able to use Foundation Medicine’s comprehensive genomic profiling (CGP) assay, FoundationOne CDx, to identify patients with FGFR2 fusions and select rearrangements who may benefit from treatment with Pemazyre in accordance with the approved therapeutic product labeling.

"The approval of this therapy and companion diagnostic is an important step forward in advancing care for patients with cholangiocarcinoma for whom there are limited treatment options," said Brian Alexander, M.D., M.P.H., chief medical officer at Foundation Medicine. "The breadth and depth of our sequencing allows for identification of patients with this rare fusion who may benefit from Pemazyre, underscoring the importance of comprehensive genomic profiling in cholangiocarcinoma. We continue to work toward broadening patient access to biomarker-driven therapies, illustrated by this recent milestone. We are proud to add another important FDA-approved companion diagnostic to FoundationOne CDx."

FoundationOne CDx is the first FDA-approved broad companion diagnostic that is clinically and analytically validated for solid tumors. It is currently approved as the companion diagnostic test for 20 unique therapies across multiple cancer types.

"Patients with rare cancers like cholangiocarcinoma often face additional challenges when it comes to available research and treatment options for their condition," said Jim Palma, Executive Director at Target Cancer Foundation. "The approval of this therapy and companion diagnostic is a turning point for these patients and the rare cancer community as a whole. Not only could it be lifechanging for cholangiocarcinoma patients with FGFR2 fusions and select rearrangements, but it reinforces the critical need for comprehensive genomic profiling and the power of collaboration among scientists, clinicians, patients and advocacy organizations."

Incyte announced earlier today the U.S. FDA approval of Pemazyre as the first selective FGFR inhibitor for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or other rearrangement as detected by an FDA-approved test. Pemazyre is a potent, selective, oral inhibitor of FGFR isoforms 1, 2 and 3 which, in preclinical studies, has demonstrated selective pharmacologic activity against cancer cells with FGFR alterations. More information about Pemazyre can be found at www.pemazyre.com.

About FoundationOne CDx

FoundationOne CDx is a next-generation sequencing based in vitro diagnostic device for detection of substitutions, insertion and deletion alterations (indels), and copy number alterations (CNAs) in 324 genes and select gene rearrangements, as well as genomic signatures including microsatellite instability (MSI) and tumor mutational burden (TMB) using DNA isolated from formalin-fixed paraffin embedded (FFPE) tumor tissue specimens. FoundationOne CDx is intended as a companion diagnostic to identify patients who may benefit from treatment with certain targeted therapies in accordance with their approved therapeutic product labeling. Additionally, FoundationOne CDx is intended to provide tumor mutation profiling to be used by qualified health care professionals in accordance with professional guidelines in oncology for patients with solid malignant neoplasms. For a full list of targeted therapies for which FoundationOne CDx is indicated as a companion diagnostic, please visit View Source

About FGFR

Fibroblast growth factor receptors (FGFRs) play an important role in tumor cell proliferation and survival, migration and angiogenesis (the formation of new blood vessels). Activating fusions, rearrangements, translocations and gene amplifications in FGFRs are closely correlated with the development of various cancers.

On April 16, 2020 Provectus (OTCQB: PVCT) reported that data from its clinical trial of autolytic cancer immunotherapy PV-10 (rose bengal disodium) as a single-agent and in combination with immune checkpoint blockade for the treatment of primary or metastatic tumors of the liver (NCT00986661) was uploaded to the SIR 2020 ePoster Gallery of the canceled Society of Interventional Radiology (SIR) 2020 Annual Scientific Meeting, which was originally scheduled to be held March 28-April 2, 2020 in Seattle, Washington (Press release, Provectus Pharmaceuticals, APR 16, 2020, View Source [SID1234556419]).

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SARS-CoV-21 note: Provectus’ ongoing clinical trials continue to enroll new patients, and patients who have been enrolled and treated on these trials still receive care.

Small molecule-based PV-10 is administered by percutaneous intratumoral injection to primary or metastatic tumors of the liver, such as hepatocellular carcinoma (HCC), metastatic colorectal cancer (mCRC), metastatic neuroendocrine tumors, and metastatic uveal melanoma (mUM). Intratumoral injection with lysosomal-targeting PV-10 yields immunogenic cell death in solid tumor cancers that results in tumor-specific reactivity in circulating T cells.2-5

This multicenter, open-label, Phase 1 basket study is evaluating PV-10’s safety, tolerability, and preliminary efficacy in unresectable cancers of the liver. PV-10 is administered under image guidance to one to three tumors of 1.0 to 4.9 cm in diameter. Response assessments (Computed Tomography [CT], Magnetic Resonance Imaging [MRI], and/or Positron Emission Tomography [PET]) are performed at day 28, and then every 12 weeks. Patients with additional injectable disease may receive further PV-10 injection after day 28. Modified Response Evaluation Criteria in Solid Tumors (mRECIST) and European Association of the Study of the Liver (2D-EASL) criteria were used to evaluate response of injected tumors; 2D-EASL response assessment measures only viable tumor tissue. PV-10 is radiopaque, which facilitates disease treatment and response follow-up.

Updated Hepatic Tumor Results from the Presentation at SIR 2020:

Baseline characteristics (N=32): 44% male; median age of 66 years (range 32-89).
Disease characteristics: HCC (7 patients), mCRC (6), mUM (13); other metastases included lung carcinoma (2), cutaneous melanoma (1), breast carcinoma (1), ovarian adenocarcinoma (1), and pancreatobiliary adenocarcinoma (1)
Safety summary: Treatment-emergent serious adverse events attributed to PV-10 were observed in 6 patients (5 patients experienced transient CTCAE Grade 3 events that resolved with sequalae; 1 patient experienced Grade 5 thrombus)
Treatment summary: 49 injected tumors (46 interventional procedures); 1 tumor injected twice
Tumor treatment patterns, response characteristics, and patient status:
HCC: 10 evaluable injected lesions by mRECIST, 30% object response rate (ORR), 90% disease control rate (DRR); 8 evaluable by 2D-EASL, 75% ORR, 100% DCR; 4 of 7 patients alive (range 0-112 months)
mCRC: 6 evaluable injected lesions by mRECIST, 67% DCR; ; 5 evaluable by 2D-EASL, 60% ORR, 60% DCR; 2 of 6 patients alive (3-97+ months)
mUM: 10 of 13 patients alive (4.6-22.7 months)
Patient survival characteristics:
HCC: median overall survival (OS) and disease-specific survival (DSS) not reached
mCRC: median 26.8 months OS and DSS (range 3-97+)
mUM: median OS and DSS not reached; initial follow-up <24 months
Dominic Rodrigues, Vice Chair of the Company’s Board of Directors, said, "These single-agent PV-10 and combination therapy data further support our drug development strategy and specific plans of developing a registrational study of the combination of PV-10, ipilimumab, and nivolumab for the treatment of uveal melanoma metastatic to the liver as well as a Phase 2 study of the combination of PV-10 and an anti-PD-(L)1 agent for first- and/or second-line treatment of hepatocellular carcinoma."

A copy of our poster presentation is available on Provectus’ website at View Source

On March 4th, SIR and SIR Foundation leadership cancelled the SIR 2020 Annual Scientific Meeting. SIR asked all presenters to upload their presentations to the SIR 2020 ePoster Portal.

About PV-10

PV-10 is undergoing clinical study for adult solid tumor cancers, like melanoma and cancers of the liver (including metastatic neuroendocrine tumors and metastatic uveal melanoma). PV-10 is also undergoing preclinical study for pediatric solid tumor cancers (like neuroblastoma, Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma) and pediatric blood cancers (like leukemia).6,7

Tumor Cell Lysosomes as the Seminal Drug Target

Lysosomes are the central organelles for intracellular degradation of biological materials, and nearly all types of eukaryotic cells have them. Discovered by Christian de Duve, MD in 1955, lysosomes are linked to several biological processes, including cell death and immune response. In 1959, de Duve described them as ‘suicide bags’ because their rupture causes cell death and tissue autolysis. He was awarded the Nobel Prize in 1974 for discovering and characterizing lysosomes, which are also linked to each of the three primary cell death pathways: apoptosis, autophagy, and necrosis.

Building on the Discovery, Exploration, and Characterization of Lysosomes

Cancer cells, particularly advanced cancer cells, are very dependent on effective lysosomal functioning.8 Cancer progression and metastasis are associated with lysosomal compartment changes9,10, which are closely correlated with (among other things) invasive growth, angiogenesis, and drug resistance11.

PV-10 selectively accumulates in the lysosomes of cancer cells upon contact, disrupting the lysosomes and causing the cell to die. Provectus2,12, external collaborators6, and other researchers13-15 have independently shown that PV-10 (RB) triggers each of the three primary cell death pathways: apoptosis, autophagy, and necrosis.

Cancer Cell Autolytic Death via PV-10: PV-10 induced autolytic cell death, or death by self-digestion, in Hepa1-6 murine HCC cells can be viewed in this Provectus video of the event (ethidium homodimer 1 [ED-1] stains DNA, but is excluded from intact nuclei; lysosensor green [LSG] stains intact lysosomes; the video is provided in 30-second frames; the event has a duration of approximately one hour). Exposure to PV-10 triggers the disruption of lysosomes, followed by nucleus failure and autolytic cell death. Identical responses have been shown by the Company in HTB-133 human breast carcinoma (which can be viewed in this Provectus video; this event has a duration of approximately two hours) and H69Ar human multidrug-resistant small cell lung carcinoma. Cancer cell autolytic cell death was reproduced by research collaborators from POETIC using relapsed and refractory human pediatric neuroblastoma cells to show that lysosomes are disrupted upon exposure to PV-10.6

Immune Signaling Pathways: PV-10 causes acute autolytic destruction of injected tumors (i.e., cell death), mediating several identified immune signaling pathways studied to date, such as the release of danger-associated molecular pattern molecules (DAMPs) and tumor antigens that initiate an immunologic cascade where local response by the innate immune system facilitates systemic anti-tumor immunity by the adaptive immune system. The DAMP release-mediated adaptive immune response activates lymphocytes, including CD8+ T cells, CD4+ T cells, and NKT cells, based on clinical and preclinical experience in multiple tumor types. Other mediated immune signaling pathways that have been identified include poly-ADP ribose polymerase (PARP) cleavage and, now, stimulator of interferon genes (STING), which plays an important role in innate immunity. PV-10 is the first cancer drug that may facilitate multiple, complementary, immune system signaling pathways.16

Orphan Drug Designations (ODDs)

ODD status has been granted to PV-10 by the U.S. Food and Drug Administration for the treatments of metastatic melanoma in 2006, hepatocellular carcinoma in 2011, neuroblastoma in 2018, and ocular melanoma (including uveal melanoma) in 2019.

Drug Product

Rose bengal disodium (RB) (4,5,6,7-tetrachloro-2’,4’,5’,7’-tetraiodofluorescein disodium salt) is a small molecule halogenated xanthene and PV-10’s active pharmaceutical ingredient. PV-10 drug product is a formulation of 10% w/v RB in 0.9% saline, supplied in single-use glass vials containing 5 mL (to deliver) of solution, and administered without dilution to solid tumors via intratumoral injection.

Intellectual Property (IP)

Provectus’ IP includes a family of US and international (a number of countries in Asia, Europe, and North America) patents that protect the process by which pharmaceutical grade RB and related halogenated xanthenes are produced, reducing the formation of previously unknown impurities that exist in commercial grade RB in uncontrolled amounts. The requirement to control these impurities is in accordance with International Council on Harmonisation (ICH) guidelines for the manufacturing of an injectable pharmaceutical. US patent numbers are 8,530,675, 9,273,022, and 9,422,260, with expirations ranging from 2030 to 2031.

The Company’s IP also includes a family of US and international (a number of countries in Asia, Europe, and North America) patents that protect the combination of PV-10 and systemic immunomodulatory therapy (e.g., anti-CTLA-4, anti-PD-1, and anti-PD-L1 agents) for the treatment of a range of solid tumor cancers. US patent numbers are 9,107,887, 9,808,524, 9,839,688, and 10,471,144, with expirations ranging from 2032 to 2035.