OMISIRGE® (Omidubicel-onlv)

The FDA on April 17, 2023, approved OMISIRGE® for use in adult and pediatric patients (12 years and older) with hematologic malignancies who are planned for umbilical cord blood transplantation following myeloablative conditioning, to reduce the time to neutrophil recovery and the incidence of infection. OMISIRGE® is a product of Gamida Cell Ltd.

Late Breaking Abstract – ASCO 2023: ENHERTU® Effective in Multiple HER2 Expressing Solid Tumors

SUMMARY: The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of invasive breast cancers as well as advanced Gastric and GastroEsophageal (GE) junction cancers overexpress or have amplification of the HER2 oncogene. These patients often receive first line treatment with a combination of chemotherapy plus anti-HER2 antibody. Several other cancer types including gynecologic and urothelial cancers overexpress HER oncogene.

ENHERTU® (Trastuzumab Deruxtecan) is an Antibody-Drug Conjugate (ADC) composed of a humanized monoclonal antibody specifically targeting HER2, with the amino acid sequence similar to Trastuzumab, a cleavable tetrapeptide-based linker, and a potent cytotoxic Topoisomerase I inhibitor as the cytotoxic drug (payload). ENHERTU® has a favorable pharmacokinetic profile and the tetrapeptide-based linker is stable in the plasma and is selectively cleaved by cathepsins that are up-regulated in tumor cells. Unlike KADCYLA® (ado-Trastuzumab emtansine), another ADC targeting HER2, ENHERTU® has a higher drug-to-antibody ratio (8 versus 4), released payload easily crosses the cell membrane with resulting potent cytotoxic effect on neighboring tumor cells regardless of target expression, and the released cytotoxic agent (payload) has a short half-life, thus minimizing systemic exposure.

ENHERTU® is approved by the FDA for use in unresectable or metastatic HER2-positive breast cancer, HER2-low breast cancer, HER2-mutant non–small cell lung cancer, and locally advanced or metastatic HER2-positive gastric cancer. ENHERTU® in a Phase I trial, demonstrated clinically meaningful activity in multiple advanced solid tumors expressing HER2 oncogene.

DESTINY-PanTumor-02 is an international, open-label Phase II study conducted to evaluate the effectiveness of ENHERTU® in patients with HER2-expressing biliary tract, bladder, cervical, endometrial, ovarian, pancreatic, or other tumors. This study involved 267 patients (N=267) across 7 different cohorts, including 6 tumor-specific cohorts (urothelial bladder, biliary tract, cervical, endometrial, ovarian, and pancreatic cancers) as well as a rare tumor cohort that included several other tumor types for which ENHERTU® is currently either not available or not being investigated (including head and neck cancers and intestinal adenocarcinoma). Patients with breast, gastric, colorectal and non-small cell lung cancers were excluded. Patients in this study had HER2-expressing (IHC 3+ or IHC 2+) locally advanced or metastatic disease that progressed after at least one systemic treatment or that had no treatment options. Among those studied 75 patients were IHC 3+ and 125 were IHC 2+ by central testing. Study patients were treated with at least one dose of ENHERTU® 5.4 mg/kg IV every 3 weeks and efficacy and safety were analyzed in all patients who received one or more doses of ENHERTU®. The Primary endpoint was investigator-assessed confirmed Objective Response Rate (ORR). Secondary endpoints included Duration of Response (DOR), Disease Control Rate, Progression Free Survival (PFS), Overall Survival, and Safety.

At data cutoff and after a median follow-up, 9.7 months, the ORR among all patients was 37.1% with a median DOR of 11.8 months. In patients with IHC 3+ expression, the ORR was 61.3% and the median DOR was 22.1 months whereas among those patients with IHC 2+ expression, the ORR was 27.2% and the median DOR was 9.8 months.

Treatment with ENHERTU resulted in the following Objective Response Rates across different tumor types:
Endometrial cancer: 57.5% for all patients, 84.6% for IHC 3+, and 47.1% for IHC 2+
Cervical cancer: 50% for all patients, 75% for IHC 3+, 40% for IHC 2+
Ovarian cancer: 45% for all patients, 63.6% for IHC 3+, 36.8% for IHC 2+
Urothelial cancer: 39% for all patients, 56.3% for IHC 3+, 35% for IHC 2+
Biliary tract cancer: 22% for all patients, 56.3% for IHC 3+, 0% for IHC 2+
Pancreatic cancer: 4% for all patients, 0% for IHC 3+, 5.3% for IHC 2+

The most common treatment-related side effects were nausea, fatigue, and cytopenias and there were no new safety signals.

It was concluded from this study results that ENHERTU® is a potential new treatment option for patients with HER2-expressing solid tumors, based on the encouraging Objective Response Rate, durable clinical benefit, and a manageable safety profile, in this heavily pretreated population. The authors added that this is the first tumor-agnostic global study of ENHERTU® in a broad range of HER2-expressing solid tumors.

Efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-expressing solid tumors: DESTINY-PanTumor02 (DP-02) interim results. Meric-Bernstam F, Makker V, Oaknin A, et al. J Clin Oncol 41, 2023 (suppl 17; abstr LBA3000)

Platelet Transfusion before Central Venous Catheter Placement in Patients with Thrombocytopenia

SUMMARY: Thrombocytopenia is a frequent finding in hospitalized patients and is one of the most common reasons for inpatient hematology consultations. Thrombocytopenia is usually defined as a platelet count of less than 150,000 per cubic millimeter, whereas severe thrombocytopenia is considered as platelet counts less than 50,000 per cubic millimeter. It is estimated that the prevalence of thrombocytopenia at admission to ICU is around 20-30% of patients, and a similar number of patients develop thrombocytopenia (from a normal platelet count) while being treated in the ICU.

Approximately 18% of hospitalized patients undergo Central Venous Catheter (CVC) placement, an invasive procedure, during admission. Central Venous Catheter facilitates simultaneous infusion of multiple medications, administration of vasoactive drugs, irritating or hypertonic solutions such as TPN, as well as hemodialysis and hemodynamic monitoring. The routine use of ultrasound guided CVC placement has greatly reduced the risk of bleeding complication. In clinical practice, platelet-transfusion thresholds range from 20,000 to 50,000 per cubic millimeter, as there is lack of good-quality evidence. It is however unclear whether the use of prophylactically transfused platelet concentrates is necessary to prevent CVC-related bleeding complications, in patients with severe thrombocytopenia.

The PACER trial is a multicenter, randomized, controlled, noninferiority study of Prophylactic Platelet Transfusion Prior to Central Venous Catheter Placement in Patients with Thrombocytopenia. This trial was conducted on hematology wards and in ICUs at 10 hospitals in the Netherlands, to evaluate whether the omission of prophylactic platelet transfusion before CVC placement in patients with a platelet count of 10,000 to 50,000 per cubic millimeter increased the risk of catheter-related bleeding. This study included 373 patients (N=373) randomized in a 1:1 ratio to receive either one unit of platelet concentrate (N=188) or no platelet transfusion (N=185) before CVC placement. CVC placement was ultrasound guided, performed by an experienced operator, could be of any diameter, could be either tunneled or nontunneled, and could be placed in the internal jugular vein, subclavian vein, or femoral vein. Randomization was stratified according to the trial center and catheter type (large-bore dialysis catheter or regular catheter). Patient characteristics at the time of CVC placement were well balanced between the two trial groups. Exclusion criteria included therapeutically administered anticoagulant, a history of congenital or acquired coagulation factor deficiency or bleeding risk, or a spontaneously prolonged INR of 1.5 or more.

The Primary outcome was the occurrence of catheter-related bleeding of Grade 2-4 within 24 hours after CVC placement. Bleeding was assessed according to the Common Terminology Criteria for Adverse Events. The occurrence of bleeding and any related treatments were recorded by trained staff members at each site immediately after CVC placement, and at 1 hour and 24 hours thereafter. A key Secondary outcome was major bleeding (Grade 3-4).

Grade 2-4 catheter-related bleeding occurred in 4.8% of patients in the platelet transfusion group and in 11.9% of patients in the no-transfusion group. The absolute risk difference was 7.1%, Relative Risk was 2.45, and noninferiority of withholding platelet transfusion was not shown. The risk of Grade 3 or 4 catheter-related bleeding was lower in the platelet transfusion group compared to the no-transfusion group (2.1% versus 4.9%), with Relative Risks consistent with the Primary outcome.

The bleeding risk in the prespecified exploratory subgroup analysis, were similar to the findings of the Primary analysis. The bleeding risk among the patients being treated on the hematology ward was higher than that among patients in the ICU, and the same was true with the use of tunneled catheters as compared with nontunneled catheters. The differences in CVC-related bleeding risk was attributed to patients in the ICU more often having consumptive thrombocytopenia, whereas patients with hematologic problems in the hematology ward more often have hypoproliferative thrombocytopenia.

It was concluded from this study that in patients with severe thrombocytopenia, withholding prophylactic platelet transfusion before Central Venous Catheter placement in those with a platelet count of 10,000 to 50,000 per cubic millimeter resulted in more catheter-related bleeding events, and prophylactic platelet transfusion was associated with a lower risk of bleeding.

Platelet Transfusion before CVC Placement in Patients with Thrombocytopenia. van Baarle FLF, van de Weerdt EK, van der Velden WJFM, et al. N Engl J Med 2023; 388:1956-1965.

Whole Exome Sequencing Identifies Cancer Predisposition Syndromes Missed by Current Screening Guidelines

SUMMARY: Hereditary factors play an important role in the risk of developing several cancers. Therefore, identification of a germline predisposition can have important implications for treatment decision making, risk-reducing interventions, cancer screening for early diagnosis, germline testing and targeted surveillance of unaffected relatives. Previously published studies have been biased by estimating the prevalence of germline cancer susceptibility in patients with breast, prostate, and colorectal cancer from registry populations, genetic testing companies, and high-risk cancer clinics.

With the widespread adoption of Next Generation Sequencing (NGS), multiple genes can be tested simultaneously (MultiGene Panel Testing-MGPT), rather than sequential single-gene testing, making MultiGene Panel Testing cheaper, faster and more efficient. Further, single-test multigene multiplexing strategy analyzes numerous cancer susceptibility genes and frequently detects highly penetrant, clinically actionable Pathogenic Germline Variants (PGV) in individuals whose clinical histories fail to fulfill syndrome-specific testing criteria. This is clinically relevant, as it has become increasingly complex to determine which individuals warrant germline testing. Several risk assessment models have been developed to provide probability of an individual carrying a germline mutation. These models provide syndrome-specific risk assessment for Lynch Syndrome, Hereditary Breast and Ovarian Cancer syndrome (HBOC)), etc.

The Genomics and Population Health Action Collaborative was formed in 2015 with the goal of identifying challenges and potential best practices for the widespread integration of evidence-based genomics applications in population health programs. They endorsed 11 genes associated with the three CDC Tier 1 inherited Autosomal Dominant cancer predisposition conditions – Hereditary Breast and Ovarian Cancer syndrome, Lynch syndrome, and Familial Hypercholesterolemia, as being a reasonable starting point for primary genomic screening in the general population.

Tapestry study is collaboration between Mayo Clinic and Helix, a population genomics company. The Tapestry trial included 44,306 patients who received treatment across Mayo Clinic sites in Minnesota, Arizona and Florida. Researchers gathered and evaluated saliva samples for pathogenic mutations in BRCA1 and BRCA2 (denoting Hereditary Breast and Ovarian Cancer), as well as MLH1, MSH2, MSH6, PMS2 and EPCAM (denoting Lynch syndrome). The mean age was 55 years, 63% were women and 90% were Caucasian. The aim of this study was to evaluate whether screening in a multisite tertiary medical center using Whole Exome Sequencing (WES) could efficiently identify carriers of two conditions, Hereditary Breast and Ovarian Cancers and Lynch syndrome, and determine the frequency of incremental carriers identified outside of traditional clinical practice guidelines.

The researchers identified 550 carriers of pathogenic mutations, including 387 individuals with Hereditary Breast and Ovarian Cancer syndrome (HBOC) and 163 with Lynch syndrome. Of these individuals with pathogenic mutations, 52.1% had no knowledge prior to this study that they carried cancer predisposition genes, and 39.2% of CARRIERS did not meet NCCN criteria for genetic testing, including 56.2% of those with Lynch syndrome and 32% of those with HBOC. Among the patients who were NEWLY DIAGNOSED with Lynch syndrome and HBOC syndrome during this study, 60% were ineligible for genetic testing per the current guidelines. They included 78% of those with Lynch syndrome and 51% of those with HBOC syndrome. Some of the reasons for not meeting NCCN criteria included having no personal history of cancer (63.3%), an insufficient number of relatives who had cancer (60.5%) and a cancer type or types not related to a genetic syndrome (58.6%). Among those who met NCCN guidelines for testing, 34.2% reported not knowing their diagnosis prior to the study. The researchers also noted that patients with HBOC or Lynch syndrome from racial and ethnic minority groups were significantly more likely than white patients to not meet NCCN screening criteria (49% versus 32%, respectively).

It was concluded that genomic screening in the broad general population for CDC Tier 1 genetic conditions has the potential to identify 50% of at-risk carriers who are otherwise not detected in current medical practice. Early diagnosis and intervention could have a positive impact on public health, and a systemic bias in the current guidelines could potentially be overcome by universal genetic testing. The authors added that the limitation of this study is that the patient population in this study may not reflect the demographics of the general population.

Exome sequencing identifies individuals with cancer predisposition syndromes missed by current screening guidelines (AACR press release). Available at: Published April 18, 2023.

XELODA® (Capecitabine tablets)

The FDA on December 14, 2022, approved updated labeling for XELODA® (Capecitabine tablets) (Xeloda, Genentech, Inc.) under Project Renewal, an Oncology Center of Excellence (OCE) initiative aimed at updating labeling information for certain older oncology drugs to ensure information is clinically meaningful and scientifically up to date. XELODA® is a product of Genentech, Inc.

RYLAZE® (Asparaginase erwinia chrysanthemi recombinant-rywn)

The FDA on November 18, 2022, approved a new Monday-Wednesday-Friday dosing regimen for RYLAZE® (Asparaginase erwinia chrysanthemi recombinant-rywn). Under the new regimen, patients should receive 25 mg/m2 intramuscularly on Monday and Wednesday mornings, and 50 mg/m2 intramuscularly on Friday afternoon. It also is approved to be administered every 48 hours at a dose of 25 mg/m2 intramuscularly. RYLAZE® is a product of Jazz Pharmaceuticals.

RETEVMO® (Selpercatinib)

The FDA on September 21, 2022, granted accelerated approval to RETEVMO® (Selpercatinib) for adult patients with locally advanced or metastatic solid tumors with a REearranged during Transfection (RET) gene fusion that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options. RETEVMO® is a product of Eli Lilly and Company.

IMBRUVICA® (Ibrutinib)

The FDA on August 24, 2022, approved IMBRUVICA® (Ibrutinib) for pediatric patients ≥ 1 year of age with chronic Graft Versus Host Disease (cGVHD) after failure of 1 or more lines of systemic therapy. Formulations include capsules, tablets, and oral suspension. IMBRUVICA® is a product of Pharmacyclics LLC.