On June 4, 2021 Gilead Sciences, Inc. (Nasdaq: GILD) reported new data from the Phase 3 ASCENT study evaluating Trodelvy (sacituzumab govitecan-hziy) in relapsed or refractory metastatic triple-negative breast cancer (TNBC) (Press release, Gilead Sciences, JUN 4, 2021, View Source [SID1234583570]). In this subgroup analysis of brain metastases-negative patients who received only one line of prior systemic therapy in the metastatic setting in addition to having disease recurrence or progression within 12 months of (neo)adjuvant chemotherapy, Trodelvy improved progression-free survival (PFS), with a 59% reduction in the risk of disease worsening or death (HR: 0.41; 95% CI: 0.22-0.76) and a median PFS of 5.7 months (n=33) versus 1.5 months with chemotherapy (n=32). Trodelvy also extended median overall survival to 10.9 months versus 4.9 months with chemotherapy (HR: 0.51; 95% CI: 0.28-0.91). The results were presented at the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Abstract #1080).

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"In patients with relapsed or refractory metastatic triple-negative breast cancer, outcomes are typically poor – especially among patients who progress within 12 months of (neo)adjuvant chemotherapy," said Lisa Carey, MD, Medical Director of the UNC Breast Center, the Physician-in-Chief of the North Carolina Cancer Hospital and Associate Director of Clinical Research at UNC Lineberger Comprehensive Cancer Center. "In the Phase 3 ASCENT study, Trodelvy was the first treatment to demonstrate a proven survival advantage in pre-treated patients with locally advanced or metastatic TNBC, and the analysis presented at ASCO (Free ASCO Whitepaper) reaffirms this benefit over standard of care with important new data in the second-line setting."

Additional results showed Trodelvy demonstrated a higher overall response rate compared with chemotherapy (30% versus 3%). Efficacy results from this subgroup were consistent with those observed in the overall ASCENT study population.

The safety profile of Trodelvy in this subgroup was consistent with prior reports. The most frequent Grade ≥3 treatment-related adverse reactions for Trodelvy compared to chemotherapy were neutropenia (61% versus 21%), leukopenia (9% versus 0%), diarrhea (6% versus 0%), anemia (3% versus 6%), and fatigue (3% versus 0%). One patient in this subgroup who received Trodelvy experienced febrile neutropenia. Adverse reactions leading to treatment discontinuation were low across both groups (6% in each). There were no treatment-related deaths with Trodelvy in this subgroup. The Trodelvy U.S. Prescribing Information has a BOXED WARNING for severe or life-threatening neutropenia and severe diarrhea; see below for Important Safety Information.

"With Trodelvy, we continue to challenge the standard of care in locally advanced and metastatic TNBC. The efficacy observed in the second-line metastatic setting with Trodelvy is highly meaningful, since many patients will progress quickly following chemotherapy. Among these patients, we see median overall survival more than doubled where need is particularly great," said Daejin Abidoye, MD, Senior Vice President, Head of Oncology Clinical Development, Gilead Sciences. "We are committed to improving the prognosis for people with this aggressive cancer, and as we continue to study Trodelvy, we are encouraged by this proven efficacy in TNBC."

Two additional ASCENT subgroup analyses that support the efficacy benefit of Trodelvy were also presented at the meeting – one evaluating Trodelvy efficacy by patients’ age (Abstract #1011) and the other comparing Trodelvy with specific single-agent chemotherapy chosen by the patients’ treating physicians (Abstract #1077).

About Triple-Negative Breast Cancer (TNBC)

TNBC is an aggressive type of breast cancer, accounting for approximately 15% of all breast cancers. The disease is diagnosed more frequently in younger and premenopausal women and is more prevalent in African American and Hispanic women. TNBC cells do not have estrogen and progesterone receptors and have limited HER2. Medicines targeting these receptors therefore are not typically effective in treating TNBC.

About the ASCENT Study

The Phase 3 ASCENT study, an open-label, active-controlled, randomized confirmatory trial, enrolled more than 500 patients with relapsed/refractory metastatic triple-negative breast cancer who had received two or more prior systemic therapies, including a taxane, at least one of them for metastatic disease. Patients were randomized to receive either Trodelvy or a chemotherapy chosen by the patients’ treating physicians. The primary efficacy outcome was PFS in patients without brain metastases at baseline, as measured by a blinded, independent, centralized review using RECIST v1.1 criteria. Additional efficacy measures included PFS for the full population, including all patients with and without brain metastases, and overall survival. More information about ASCENT is available at View Source

About Trodelvy

Trodelvy (sacituzumab govitecan-hziy) is a first-in-class antibody and topoisomerase inhibitor conjugate directed to the Trop-2 receptor, a protein frequently expressed in multiple types of epithelial tumors, including metastatic triple-negative breast cancer and metastatic urothelial cancer, where high expression is associated with poor survival and relapse.

In the U.S., Trodelvy is indicated for the treatment of:

Adult patients with unresectable locally advanced or metastatic triple-negative breast cancer who have received two or more prior systemic therapies, at least one of them for metastatic disease.
Adult patients with locally advanced or metastatic urothelial cancer who have previously received a platinum-containing chemotherapy and either programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor.
Beyond the regulatory approvals of Trodelvy in the U.S., regulatory reviews for Trodelvy in metastatic triple-negative breast cancer are currently underway in the EU, U.K., Canada, Switzerland and Australia, as well as in Singapore through our partner Everest Medicines. Trodelvy is also being investigated as potential treatment for hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer and metastatic non-small cell lung cancer. Additional evaluation across multiple solid tumors is also underway.

U.S. Important Safety Information for Trodelvy

BOXED WARNING: NEUTROPENIA AND DIARRHEA

Severe or life-threatening neutropenia may occur. Withhold Trodelvy for absolute neutrophil count below 1500/mm3 or neutropenic fever. Monitor blood cell counts periodically during treatment. Consider G-CSF for secondary prophylaxis. Initiate anti-infective treatment in patients with febrile neutropenia without delay.
Severe diarrhea may occur. Monitor patients with diarrhea and give fluid and electrolytes as needed. Administer atropine, if not contraindicated, for early diarrhea of any severity. At the onset of late diarrhea, evaluate for infectious causes and, if negative, promptly initiate loperamide. If severe diarrhea occurs, withhold Trodelvy until resolved to ≤Grade 1 and reduce subsequent doses.
CONTRAINDICATIONS

Severe hypersensitivity reaction to Trodelvy.
WARNINGS AND PRECAUTIONS

Neutropenia: Severe, life-threatening, or fatal neutropenia can occur and may require dose modification. Neutropenia occurred in 61% of patients treated with Trodelvy. Grade 3-4 neutropenia occurred in 47% of patients. Febrile neutropenia occurred in 7%. Withhold Trodelvy for absolute neutrophil count below 1500/mm3 on Day 1 of any cycle or neutrophil count below 1000/mm3 on Day 8 of any cycle. Withhold Trodelvy for neutropenic fever.

Diarrhea: Diarrhea occurred in 65% of all patients treated with Trodelvy. Grade 3-4 diarrhea occurred in 12% of patients. One patient had intestinal perforation following diarrhea. Neutropenic colitis occurred in 0.5% of patients. Withhold Trodelvy for Grade 3-4 diarrhea and resume when resolved to ≤Grade 1. At onset, evaluate for infectious causes and if negative, promptly initiate loperamide, 4 mg initially followed by 2 mg with every episode of diarrhea for a maximum of 16 mg daily. Discontinue loperamide 12 hours after diarrhea resolves. Additional supportive measures (e.g., fluid and electrolyte substitution) may also be employed as clinically indicated. Patients who exhibit an excessive cholinergic response to treatment can receive appropriate premedication (e.g., atropine) for subsequent treatments.

Hypersensitivity and Infusion-Related Reactions: Serious hypersensitivity reactions including life-threatening anaphylactic reactions have occurred with Trodelvy. Severe signs and symptoms included cardiac arrest, hypotension, wheezing, angioedema, swelling, pneumonitis, and skin reactions. Hypersensitivity reactions within 24 hours of dosing occurred in 37% of patients. Grade 3-4 hypersensitivity occurred in 2% of patients. The incidence of hypersensitivity reactions leading to permanent discontinuation of Trodelvy was 0.3%. The incidence of anaphylactic reactions was 0.3%. Pre-infusion medication is recommended. Observe patients closely for hypersensitivity and infusion-related reactions during each infusion and for at least 30 minutes after completion of each infusion. Medication to treat such reactions, as well as emergency equipment, should be available for immediate use. Permanently discontinue Trodelvy for Grade 4 infusion-related reactions.

Nausea and Vomiting: Nausea occurred in 66% of all patients treated with Trodelvy and Grade 3 nausea occurred in 4% of these patients. Vomiting occurred in 39% of patients and Grade 3-4 vomiting occurred in 3% of these patients. Premedicate with a two or three drug combination regimen (e.g., dexamethasone with either a 5-HT3 receptor antagonist or an NK1 receptor antagonist as well as other drugs as indicated) for prevention of chemotherapy-induced nausea and vomiting (CINV). Withhold Trodelvy doses for Grade 3 nausea or Grade 3-4 vomiting and resume with additional supportive measures when resolved to Grade ≤1. Additional antiemetics and other supportive measures may also be employed as clinically indicated. All patients should be given take-home medications with clear instructions for prevention and treatment of nausea and vomiting.

Increased Risk of Adverse Reactions in Patients with Reduced UGT1A1 Activity: Patients homozygous for the uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1)*28 allele are at increased risk for neutropenia, febrile neutropenia, and anemia and may be at increased risk for other adverse reactions with Trodelvy. The incidence of Grade 3-4 neutropenia was 67% in patients homozygous for the UGT1A1*28, 46% in patients heterozygous for the UGT1A1*28 allele and 46% in patients homozygous for the wild-type allele. The incidence of Grade 3-4 anemia was 25% in patients homozygous for the UGT1A1*28 allele, 10% in patients heterozygous for the UGT1A1*28 allele, and 11% in patients homozygous for the wild-type allele. Closely monitor patients with known reduced UGT1A1 activity for adverse reactions. Withhold or permanently discontinue Trodelvy based on clinical assessment of the onset, duration and severity of the observed adverse reactions in patients with evidence of acute early-onset or unusually severe adverse reactions, which may indicate reduced UGT1A1 function.

Embryo-Fetal Toxicity: Based on its mechanism of action, Trodelvy can cause teratogenicity and/or embryo-fetal lethality when administered to a pregnant woman. Trodelvy contains a genotoxic component, SN-38, and targets rapidly dividing cells. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Trodelvy and for 6 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Trodelvy and for 3 months after the last dose.

ADVERSE REACTIONS

In the ASCENT study (IMMU-132-05), the most common adverse reactions (incidence ≥25%) were fatigue, neutropenia, diarrhea, nausea, alopecia, anemia, constipation, vomiting, abdominal pain, and decreased appetite. The most frequent serious adverse reactions (SAR) (>1%) were neutropenia (7%), diarrhea (4%), and pneumonia (3%). SAR were reported in 27% of patients, and 5% discontinued therapy due to adverse reactions. The most common Grade 3-4 lab abnormalities (incidence ≥25%) in the ASCENT study were reduced neutrophils, leukocytes, and lymphocytes.

In the TROPHY study (IMMU-132-06), the most common adverse reactions (incidence ≥25%) were diarrhea, fatigue, neutropenia, nausea, any infection, alopecia, anemia, decreased appetite, constipation, vomiting, abdominal pain, and rash. The most frequent serious adverse reactions (SAR) (≥5%) were infection (18%), neutropenia (12%, including febrile neutropenia in 10%), acute kidney injury (6%), urinary tract infection (6%), and sepsis or bacteremia (5%). SAR were reported in 44% of patients, and 10% discontinued due to adverse reactions. The most common Grade 3-4 lab abnormalities (incidence ≥25%) in the TROPHY study were reduced neutrophils, leukocytes, and lymphocytes.

DRUG INTERACTIONS

UGT1A1 Inhibitors: Concomitant administration of Trodelvy with inhibitors of UGT1A1 may increase the incidence of adverse reactions due to potential increase in systemic exposure to SN-38. Avoid administering UGT1A1 inhibitors with Trodelvy.

UGT1A1 Inducers: Exposure to SN-38 may be substantially reduced in patients concomitantly receiving UGT1A1 enzyme inducers. Avoid administering UGT1A1 inducers with Trodelvy.

On June 4, 2021 Agendia, Inc., a world leader in precision oncology for breast cancer, reported that new data from the first-of-its kind, national FLEX registry was debuted today at the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Press release, Agendia, JUN 4, 2021, View Source [SID1234583584]).

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The FLEX study is led by clinicians across the United States and utilizes a shared study infrastructure to develop and investigate hypotheses for targeted patient subsets based on full transcriptome data, and annotated with over 800 clinical data elements. FLEX allows for diverse groups of patients and their physicians to participate in a clinical trial even if they are not living near a major research center.

"FLEX has continued to show its value in the enormous breadth of growing data we as oncologists and researchers can access," said Cynthia X. Ma, MD, PhD, oncologist and FLEX national PI at Washington University School of Medicine in St. Louis. "The collaborative nature of the registry gives physicians the chance to investigate the hypotheses formed in our real-world practices on a national level, to answer questions of both clinical importance and scientific interest. The depth and clinical significance of our findings are felt throughout the breast cancer community."

At the virtual ASCO (Free ASCO Whitepaper) 2021 conference, Agendia and its research collaborators provided a general update on the currently enrolling FLEX trial in a poster titled "The FLEX real-world data platform explores new gene expression profiles and investigator-initiated protocols in early stage breast cancer."

The power of FLEX to address relevant and pressing clinical questions was illustrated by data presented in a poster entitled "Whole transcriptome analysis comparing HR+ HER2- breast cancer tumors from patients <50 years and >50 years." The study showed that whole transcriptome analysis identified no substantial differences in gene expression between HR+/HER2- tumors in women with breast cancer, regardless of their age (over or under 50 years old). The data support the likely explanation that the apparent age-dependent benefit of chemotherapy in women younger than 50 with genomically Low Risk cancer, observed in recent trials, is not due to intrinsic biological differences in breast cancer, but rather to differences in the indirect effects of chemotherapy on the patient. These findings reinforce the essential need for shared decision making between a patient and her physician using the patient’s genomic expression profile as part of an informed treatment plan.

"We are excited to present an age-based analysis of the genomics in early stage breast cancer which has garnered so much attention in the last couple of years," said Cathy Graham, MD, FACS, Director of Breast Surgery, Glenn Family Breast Center of Winship Cancer Institute at Emory Saint Joseph’s Hospital, and first author of a FLEX poster focused on age-based analysis. "The trend that has emerged, which suggests that chemotherapy benefit seen in younger women may be a side effect of ovarian suppression – not necessarily the cytotoxic effects of the chemo on a tumor – is seen again in these results and must be considered when potentially less-aggressive alternatives are available."

Additional data of clinical significance for high risk ER+ breast cancer were presented by FLEX investigators including Joyce O’Shaughnessy, MD, Co-Chair of Breast Cancer Research and Chair of Breast Cancer Prevention Research at Baylor-Sammons Cancer Center and for The US Oncology Network, and a member of the Scientific Advisory Board for US Oncology Research Network, in the poster titled "Molecular profiles of genomically High Risk ER+ HER2- breast cancer tumors classified as functionally Basal or Luminal B by the 80-gene signature." This study outlined the identification by BluePrint of a subgroup of high risk ER+ tumors that are genomically Basal, and showed that analysis of whole transcriptome expression profiles reveals these cancers to be biologically closer to ER- Basal (and triple negative breast cancer) than ER+ Luminal cancers. ER+ Basal tumors may therefore require more aggressive treatment than ER+ Luminal tumors, confirming that BluePrint provides clinically actionable information beyond pathological subtyping and may guide neoadjuvant treatment decisions.

A further study from the FLEX database analyzed the correlation between a traditional poor prognosis pathology feature, lymphovascular invasion (LVI), and gene expression patterns. The study, titled "Gene expression associated with lymphovascular invasion and genomic risk in early-stage breast cancer," was presented by Nina D’Abreo, MD, medical director, breast program, Winthrop University Hospital, Perlmutter Cancer Center, and her colleagues, and showed that the potential prognostic information gained from the presence or absence of lymphovascular invasion (LVI) gene expression is likely already captured by MammaPrint and BluePrint. Importantly, presence or absence of LVI in MammaPrint Low Risk cancers was not associated with any discernible differences in whole transcriptome gene expression. LVI is currently excluded from most breast cancer clinical risk assessments, and while further studies will assess clinical outcomes, these data suggest that MammaPrint and BluePrint may be able to address a current gap in stratification of early stage breast cancers.

Agendia’s large-scale, prospective FLEX study continues to provide a rich source of data from real-world evidence in one of the most dynamic and inclusive study designs in breast cancer research to date, underscoring the company’s mission to help guide the diagnosis and personalized treatment of breast cancer for all patients.

On June 4, 2021 Amphivena Therapeutics, a clinical-stage oncology company focused on developing immune-therapeutics that restore anti-cancer immunity to patients, reported a favorable safety profile for AMV564 and clinical responses including a CR in patients with advanced relapsed or refractory solid tumors (Press release, Amphivena Therapeutics, JUN 4, 2021, View Source [SID1234583602]). The poster presentation at the 2021 virtual American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting disclosed the first comprehensive set of clinical results from Amphivena’s Phase 1 dose escalation study of AMV564 dosed subcutaneously (sc) as monotherapy or in combination with pembrolizumab, including in post checkpoint treatment failures.

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Poster authors representing Duke University, The Christ Hospital of Cincinnati, OH, MD Anderson Cancer Center, NEXT Oncology, and Moffitt Cancer Center concluded that AMV564 delivered subcutaneously was well tolerated with no dose-limiting toxicities and no maximum tolerated dose reported. Additionally, clinical responses were observed in both monotherapy and combination therapy patients, including durable stable disease, mixed responses, and a RECIST v1.1 complete response (ovarian cancer patient treated with AMV564 monotherapy). Importantly, no cases of CRS were observed at the planned dose expansion doses.

According to Patrick Chun, M.D., Amphivena vice president of clinical development, "T cell engagement has proven to be a viable immunotherapeutic strategy in cancer. However, previous technologies have been limited by toxicity (CRS), exposure, and attenuated efficacy. With this data, we are clearly differentiating Amphivena from other companies in the space. Our unique approach uses T cell engagers that target MDSCs, thus attenuating the immunosuppressive milieu in cancer patients, while simultaneously limiting CRS, which has been the primary adverse event of concern with this class of molecules. Based on the clinical safety and pharmacokinetic profiles, along with clinical activity, we believe it is imperative to further explore AMV564 in selected solid tumor indications and alternative dosing regimens, including once weekly dosing."

The poster presents data that AMV564 induced expansion of tumor-specific T-cell clones and clinical responses when administered as a monotherapy and in combination with a checkpoint inhibitor, including in patients who have previously progressed with checkpoint inhibitor treatment. Strong induction of IFNγ was observed with monotherapy and especially in combination, with comparatively low IL6, favorable with respect to both safety and induction of anti-tumor response pathways.

The Phase 1 dose escalation study (NCT04128423) enrolled 30 patients (20 monotherapy, 10 combination therapy). The majority of patients received three or more lines of prior therapy (70% of monotherapy patients, 50% of combination therapy patients) including 35% of monotherapy patients and 10% of combination therapy patients who received prior checkpoint-inhibitor therapy.

Details of the Presentations:

Title: Results of a phase 1 dose-escalation study of AMV564, a novel T-cell engager, alone and in combination with pembrolizumab in patients with relapsed/refractory solid tumors
Authors: Niharika B. Mettu, et al.
Abstract Number: 2555

The full abstract and poster will be available on the ASCO (Free ASCO Whitepaper) Annual Meeting 2021 and Amphivena website (View Source) as of 9:00AM EDT on Friday, June 4th.

About AMV564

AMV564 is a product of Amphivena’s proprietary ReSTORETM (Relieve Suppression of T cells in Oncology and Reinvigorate Effectors) platform of bivalent T-cell engagers. The investigational drug candidate has been shown to relieve immune suppression via targeted depletion of immunosuppressive MDSC and drive T cell activation and polarization to restore anti-cancer immunity. To date, over 80 patients have received AMV564 across three Phase 1 clinical trials for patients with solid tumors, acute myeloid leukemia (AML), and myelodysplastic syndromes (MDS).

On June 4, 2021 Exelixis, Inc. (NASDAQ: EXEL) reported promising phase 2 results for CABOMETYX (cabozantinib) in combination with Bristol Myers Squibb’s OPDIVO (nivolumab) in patients with advanced or metastatic non-clear cell renal cell carcinoma (nccRCC) from an investigator-sponsored trial (Press release, Exelixis, JUN 4, 2021, View Source [SID1234583502]). The combination regimen showed promising efficacy and an acceptable safety profile in patients with metastatic nccRCC with papillary, unclassified or translocation-associated histologies. The data will be presented as part of the Poster Discussion Session: Genitourinary Cancer – Kidney and Bladder at the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, which is being held virtually, June 4-8, 2021. All posters will be available on demand beginning at 6:00 a.m. PT on Friday, June 4.

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"The strong objective response rate associated with cabozantinib in combination with nivolumab in this trial is a meaningful finding for this patient community, who are typically not the focus of major clinical trials for kidney cancer," said Dr. Chung-Han Lee, medical oncologist at Memorial Sloan Kettering Cancer Center, and principal investigator for the study. "We look forward to building on these results with additional insights into which types of non-clear cell renal cell carcinoma may be most likely to respond to this combination regimen."

This single-institution, non-randomized, open-label, investigator-sponsored, phase 2 trial of CABOMETYX 40 mg in combination with OPDIVO (240 mg every two weeks or 480 mg every four weeks) was conducted by Memorial Sloan Kettering Cancer Center. The trial enrolled patients with advanced or metastatic nccRCC who had not received prior immune checkpoint inhibitor (ICI) therapy. A total of 47 patients were treated; 40 patients with papillary, unclassified, or translocation-associated RCC in cohort 1, and seven patients with chromophobe histology in cohort 2. Median follow-up was 13.1 months.

In cohort 1, CABOMETYX in combination with OPDIVO demonstrated an objective response rate (ORR) of 47.5% (95% confidence interval [CI]: 31.5–63.9). Among the 32 patients with papillary histology, ORR was 47% (95% CI: 29–65). Objective responses were seen in five of six patients with NF2 mutations, four of five patients with FH mutations and one of six patients with SETD2 mutations. Median duration of response was 13.6 months. Median progression-free survival was 12.5 months (95% CI: 6.3–15.9), and median overall survival was 28 months (95% CI: 16.3–non-estimable). A best response of stable disease was observed for five of seven patients in cohort 2.

"Following the recent FDA approval of CABOMETYX in combination with OPDIVO as a first-line treatment for patients with advanced renal cell carcinoma, we’re excited to see these new data specifically in non-clear cell RCC, a heterogeneous group of kidney cancers," said Gisela Schwab, M.D., President, Product Development and Medical Affairs and Chief Medical Officer, Exelixis. "These positive phase 2 results build on our understanding of CABOMETYX’s potential use in papillary RCC, one of these subtypes, and may help physicians choose an appropriate first-line systemic therapy for their patients with advanced non-clear cell renal cell carcinoma."

CABOMETYX or OPDIVO was discontinued due to adverse events in 17% and 13% of patients, respectively. Both therapies were discontinued due to adverse events in 9% of patients. Grade 3/4 treatment-related adverse events were observed in 32% of patients. The most common grade 3/4 treatment-related adverse events were hypertension (13%) and diarrhea (6%).

More information about this trial (NCT03635892) is available at ClinicalTrials.gov.

About RCC

The American Cancer Society’s 2021 statistics cite kidney cancer as among the top ten most commonly diagnosed forms of cancer among both men and women in the U.S.1 If detected in its early stages, the five-year survival rate for RCC is high; for patients with advanced or late-stage metastatic RCC, however, the five-year survival rate is only 13%.1 Approximately 32,000 patients in the U.S. and 71,000 worldwide will require systemic treatment for advanced kidney cancer in 2021.2

About 70% of RCC cases are known as "clear cell" carcinomas, based on histology.3 Other subtypes, collectively grouped as nccRCC, constitute a diverse mixture of malignancies.4 Papillary histology accounts for about 15% of all renal cell carcinomas.5,6 Genomic and molecular characterization of papillary RCC has implicated MET signaling as a key driver of this cancer.6,7 Targeting VEGFR and other tyrosine kinases, including MET and AXL, has led to improved outcomes in RCC compared with sunitinib and further supported the investigation of MET-targeting tyrosine kinase inhibitors in nccRCC.

About CABOMETYX (cabozantinib)

In the U.S., CABOMETYX tablets are approved for the treatment of patients with advanced RCC; for the treatment of patients with HCC who have been previously treated with sorafenib; and for patients with advanced RCC as a first-line treatment in combination with OPDIVO. CABOMETYX tablets have also received regulatory approvals in the European Union and additional countries and regions worldwide. In 2016, Exelixis granted Ipsen exclusive rights for the commercialization and further clinical development of cabozantinib outside of the United States and Japan. In 2017, Exelixis granted exclusive rights to Takeda Pharmaceutical Company Limited for the commercialization and further clinical development of cabozantinib for all future indications in Japan. Exelixis holds the exclusive rights to develop and commercialize cabozantinib in the United States.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Severe and fatal hemorrhages occurred with CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX patients in RCC and HCC studies. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.

Perforations and Fistulas: Fistulas, including fatal cases, occurred in 1% of CABOMETYX patients. Gastrointestinal (GI) perforations, including fatal cases, occurred in 1% of CABOMETYX patients. Monitor patients for signs and symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a Grade 4 fistula or a GI perforation.

Thrombotic Events: CABOMETYX increased the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events occurred in CABOMETYX patients. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events that require medical intervention.

Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension was reported in 36% (17% Grade 3 and <1% Grade 4) of CABOMETYX patients. Do not initiate CABOMETYX in patients with uncontrolled hypertension. Monitor blood pressure regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume at a reduced dose. Discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.

Diarrhea: Diarrhea occurred in 63% of CABOMETYX patients. Grade 3 diarrhea occurred in 11% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 diarrhea, Grade 3 diarrhea that cannot be managed with standard antidiarrheal treatments, or Grade 4 diarrhea.

Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in 44% of CABOMETYX patients. Grade 3 PPE occurred in 13% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.

Hepatotoxicity: CABOMETYX in combination with nivolumab can cause hepatic toxicity with higher frequencies of Grades 3 and 4 ALT and AST elevations compared to CABOMETYX alone.

Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes than when the drugs are administered as single agents. For elevated liver enzymes, interrupt CABOMETYX and nivolumab and consider administering corticosteroids.

With the combination of CABOMETYX and nivolumab, Grades 3 and 4 increased ALT or AST were seen in 11% of patients. ALT or AST >3 times ULN (Grade ≥2) was reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST resolved to Grades 0-1 in 74 (89%). Among the 44 patients with Grade ≥2 increased ALT or AST who were rechallenged with either CABOMETYX (n=9) or nivolumab (n=11) as a single agent or with both (n=24), recurrence of Grade ≥2 increased ALT or AST was observed in 2 patients receiving CABOMETYX, 2 patients receiving nivolumab, and 7 patients receiving both CABOMETYX and nivolumab.

Adrenal Insufficiency: CABOMETYX in combination with nivolumab can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold CABOMETYX and/or nivolumab depending on severity.

Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received CABOMETYX with nivolumab, including Grade 3 (2.2%), and Grade 2 (1.9%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of CABOMETYX and nivolumab in 0.9% and withholding of CABOMETYX and nivolumab in 2.8% of patients with RCC.

Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 patients. Of the 9 patients in whom CABOMETYX with nivolumab was withheld for adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all (n=6) received hormone replacement therapy and 2 had recurrence of adrenal insufficiency.

Proteinuria: Proteinuria was observed in 7% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. Discontinue CABOMETYX in patients who develop nephrotic syndrome.

Osteonecrosis of the Jaw (ONJ): ONJ occurred in <1% of CABOMETYX patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain, or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to CABOMETYX initiation and periodically during treatment. Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold CABOMETYX for development of ONJ until complete resolution.

Impaired Wound Healing: Wound complications occurred with CABOMETYX. Withhold CABOMETYX for at least 3 weeks prior to elective surgery. Do not administer CABOMETYX for at least 2 weeks after major surgery and until adequate wound healing is observed. The safety of resumption of CABOMETYX after resolution of wound healing complications has not been established.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic findings on MRI, can occur with CABOMETYX. Evaluate for RPLS in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.

Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Verify the pregnancy status of females of reproductive potential prior to initiating CABOMETYX and advise them to use effective contraception during treatment and for 4 months after the last dose.

ADVERSE REACTIONS

The most common (≥20%) adverse reactions are:

CABOMETYX as a single agent: diarrhea, fatigue, decreased appetite, PPE, nausea, hypertension, vomiting, weight decreased, constipation, and dysphonia.

CABOMETYX in combination with nivolumab: diarrhea, fatigue, hepatotoxicity, PPE, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.

DRUG INTERACTIONS

Strong CYP3A4 Inhibitors: If coadministration with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage. Avoid grapefruit or grapefruit juice.

Strong CYP3A4 Inducers: If coadministration with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage. Avoid St. John’s wort.

USE IN SPECIFIC POPULATIONS

Lactation: Advise women not to breastfeed during CABOMETYX treatment and for 4 months after the final dose.

Hepatic Impairment: In patients with moderate hepatic impairment, reduce the CABOMETYX dosage. Avoid CABOMETYX in patients with severe hepatic impairment.

Please see accompanying full Prescribing Information View Source

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088.

Dr. Lee has provided advisory services to Exelixis and Bristol Myers Squibb.

On June 4, 2021 Precision BioSciences Inc. (Nasdaq: DTIL), a clinical stage biotechnology company developing allogeneic CAR T and in vivo gene correction therapies with its ARCUS genome editing platform, reported encouraging progress on two strategies designed to optimize the durability of allogeneic CAR T therapy in patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL) (Press release, Precision Biosciences, JUN 4, 2021, View Source [SID1234583521]). The Company reported updated interim results from its Phase 1/2a study of PBCAR0191, the Company’s investigational, off-the-shelf, allogeneic CAR T cell therapy targeting CD19. As of May 21, 2021, 12 patients with R/R NHL were enrolled and evaluated for response to PBCAR0191 with enhanced lymphodepletion (eLD). The Company also reported preclinical data demonstrating the potential mechanism by which its investigational immune evading stealth cell, PBCAR19B, may avoid rejection by T cells and natural killer (NK) cells.

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"These interim results in heavily pretreated R/R NHL patients illustrate the potential for PBCAR0191 to recognize and target CD19 positive cancer cells and suggest that enhanced lymphodepletion may be a strategy to help suppress host immune rejection. We’re encouraged by the high initial response rates and look forward to monitoring the responses for evidence of long-term durability," said Alan List, MD, Chief Medical Officer of Precision BioSciences. "In addition, our PBCAR19B Phase 1 study is open for enrollment, and we believe this candidate has the potential to build on the encouraging clinical responses we’ve seen with PBCAR0191 to date and reduce the need for prolonged immunosuppression."

As of May 21, 2021, 18 subjects in the Phase 1/2a study of PBCAR0191 with R/R NHL completed Day 28 evaluation and received either eLD1 (n=12) or standard lymphodepletion2 (sLD; n=6) with Dose Level 33 of PBCAR0191.

Efficacy

Use of eLD mitigated PBCAR0191 rejection and markedly increased peak cell expansion (~72x) and area under the curve (AUC) (~59x), each as compared to sLD.
A single dose of PBCAR0191 cells following eLD yielded clinical responses in the majority of patients, with overall response rates (ORR) and complete response (CR) rates of 75% and 50%, respectively at Day ≥ 28.
Five of nine responding patients (56%) who received PBCAR0191 cells following eLD remained progression-free, including 4/9 evaluable subjects with responses lasting > 4 months. Assessment of duration of response is on-going.
Median interval from confirmation of eligibility to start of LD was 1 day, reinforcing the potential feasibility for rapid delivery of off-the-shelf, allogeneic, cellular therapy for high-risk patients.
Day ≥ 28 Evaluation

* Three of four responding patients had prior auto-SCT and auto CD19 CAR treatment.

Safety and Tolerability

As of May 21, 2021, PBCAR0191 with eLD continued to show acceptable tolerability without evidence of graft versus host disease (GvHD) and with a similar frequency of immune effector cell-associated neurotoxicity syndrome (ICANS) and cytokine release syndrome (CRS) compared to patients who received sLD. Infections occurred more frequently when PBCAR0191 was dosed following eLD.

Adverse Event Max Grade

(Graft versus host disease)

Three treatment emergent deaths without disease progression occurred, including two cases of infection and one case of cardiac arrest after a choking incident. Two of these patients were in ongoing complete responses at time of death. Only one death, as previously reported on December 4, 2020 was assessed by the investigator as possibly related to study treatment.

Demographics for Enrolled R/R NHL Patients (PBCAR0191 with eLD)

Over 80% of subjects had advanced and aggressive lymphomas.
75% had stage III/IV disease.
Subjects had received a median of seven lines of therapy prior to study enrollment.
33% of subjects had prior CD19-directed CAR therapy.
PBCAR19B Immune Evading Stealth Cell

PBCAR19B is designed to extend persistence of allogeneic CAR T cells by evading rejection by the immune system of the patient. In preclinical studies, the anti-CD19 PBCAR19B stealth cell exhibited substantial resistance to rejection mediated by both allo-reactive T cell and NK cells, suggesting the potential utility of this approach.

In January 2021, Precision announced that the U.S. Food and Drug Administration accepted its investigational new drug application to evaluate the safety and clinical activity of PBCAR19B in patients with R/R NHL. Initial clinical trial sites have been selected for the Phase 1 study that is now open for enrollment. PBCAR19B will be evaluated at increasing flat dose levels beginning at 2.7 x 108 cells using sLD with the ability to dose up to 8.1 x 108 cells. Of note, the first dose level is approximately equivalent to Dose Level 3 in the PBCAR0191 trial.

Company-Hosted Conference Call and Web Cast Information

Precision will host a conference call and webcast today, Friday, June 4, 2021 at 8:00 a.m. ET to discuss the most recent interim clinical data for PBCAR0191 and preclinical data for PBCAR19B. The dial-in conference call numbers for domestic and international callers are (866) 996-7202 and (270) 215-9609, respectively. The conference ID number for the call is 5647916. Participants may access the live webcast and the accompanying presentation materials on Precision’s website www.precisionbiosciences.com in the Investors and Media section under Events and Presentations. An archived replay of the webcast will be available on Precision’s website.

About PBCAR0191 and Study Design (Clinical Trials Study Identifier: NCT03666000)

PBCAR0191 is an investigational allogeneic chimeric antigen receptor T cell therapy (CAR T) in a Phase 1/2a trial for the treatment of patients with R/R NHL and R/R B-ALL. PBCAR0191 was designed using Precision BioSciences novel and proprietary ARCUS genome editing platform. It has been granted Fast Track Designation by the FDA for B-ALL. Precision also holds Orphan Drug Designation from the FDA for this program in mantle cell lymphoma, an aggressive subtype of NHL.

About PBCAR19B (Clinical Trials Study Identifier: NCT04649112)

PBCAR19B is a next-generation, stealth cell candidate for patients with CD19-positive malignancies such as R/R NHL. PBCAR19B is designed to improve the persistence of allogeneic CAR T cells following infusion by reducing rejection by T cells and NK cells. In addition to the CAR gene, the PBCAR19B stealth cell vector carries a short hairpin RNA that suppresses expression of beta-2 microglobulin, a component of Major Histocompatibility Complex (MHC) Class I molecules found on the cell surface. Reducing or knocking-down Class I MHC expression on allogeneic CAR T cells has been shown to reduce CAR T cell killing by cytotoxic allo-reactive T cells. Additionally, in an effort to attenuate NK cell-mediated elimination due to MHC class I knockdown, the PBCAR19B vector also carries an HLA-E gene designed to inactivate NK cells.