Category: Cancer and neoplasms

Scott Kopetz, MD, PhD, FACP, professor, Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses the phase 3 BREAKWATER trial (NCT04607421) in patients with BRAF V600E–mutant metastatic colorectal cancer (mCRC). The phase 3 trial evaluated encorafenib (Braftovi) plus cetuximab (Erbitux) with or without mFOLFOX6 or FOLFIRI vs chemotherapy alone in this patient population. Kopetz shares that the trial investigators are encouraged by the response rates that were reported, adding that biomarker findings were integrated into the data as well. One emerging biomarker is circulating tumor DNA (ctDNA), Kopetz says. In patients with BRAF V600E mutations, investigators can measure BRAF V600E–mutated ctDNA and track how it changes with treatment, he explains. Most patients in the phase 3 trial who received chemotherapy combined with encorafenib and cetuximab had complete clearance of their BRAF V600E–mutant ctDNA, Kopetz emphasizes. Although this is an encouraging sign of efficacy, it does not mean that these tumors are completely eradicated, but rather that the amount of disease has been driven below the limits of detection. Overall, the BREAKWATER investigators are excited by both the safety and efficacy data, Kopetz continues, adding that the BRAF V600E–mutant mCRC population needs new and innovative treatment strategies. Further research and new therapeutic approaches, such as bringing targeted therapies into earlier lines of therapy, may improve outcomes for these patients, Kopetz explains. Moreover, by combining these new approaches with cytotoxic chemotherapy, investigators may harness some of the biological synergy between these combinations, Kopetz adds. Overall, these new approaches are anticipated to improve responses, progression-free survival, and ultimately, overall survival for this population, he concludes.

The FDA has granted a breakthrough device designation to HLA-LOH as a companion diagnostic test, according to an announcement from Tempus.1 The test features a machine-learning model designed to analyze data from the next-generation sequencing (NGS)–based xT CDx assay, which is a 648-gene NGS assay for solid tumor profiling and a companion diagnostic for patients with colorectal cancer that received FDA approval in May 2023.2 The assay is designed to identify patients with solid tumors who may benefit from specific targeted therapies if their tumors underwent allele-specific loss of heterozygosity (LOH) for specific HLA class I alleles.1 “HLA-LOH provides a clear molecular distinction between cancer and non-cancer cells and is a potential biomarker for immune therapy resistance. The Tempus HLA-LOH test is intended to measure this biomarker and better understand which patients may respond to new therapies. This breakthrough device designation from the FDA recognizes the novelty and potential clinical impact of our HLA-LOH test for this promising biomarker,” Kate Sasser, PhD, chief scientific officer of Tempus, stated in a news release. “HLA-LOH is of special interest for the application of cell therapy to treat solid tumors, but also has broader potential for other precision medicine approaches in oncology, including in combination with other established biomarkers,” Sasser added. “The Tempus test is being developed to identify HLA-LOH and may help optimize existing therapies and facilitate the advancement and implementation of novel and transformative treatments.” xT CDx is a qualitative NGS-based in vitro diagnostic device designed to identify substitutions such as single nucleotide and multinucleotide variants, as well as insertion and deletion alterations in 648 genes. Additionally, it is capable of detecting microsatellite instability status through DNA isolated from formalin-fixed paraffin embedded tumor tissue specimens and DNA isolated from matched normal blood or saliva from patients with previously diagnosed solid malignant neoplasms.2 For patients with CRC, xT CDx can be utilized as a companion diagnostic to identify those with KRAS wild-type disease (absence of mutations in codons 12 or 13) who could benefit from treatment with cetuximab (Erbitux), or those who could be eligible for treatment with panitumumab (Vectibix) through the detection of KRAS wild-type (absence of mutations in exons 2, 3, and 4) and NRAS wild-type (absence of mutations in exons 2, 3, or 4) disease.3 The detection of alterations by xT CDx was compared with data from an externally validated orthogonal method (OM), with 114 overlapping genes between the 2 assays. Samples of 416 patients across 31 different tumor types were used to compare the detections of mutations, insertions, and deletions between the 2 methods. The samples were derived from patients with CRC (n = 69), breast cancer (n = 44), ovarian cancer (n = 38), glioblastoma (n = 34), non–small cell lung cancer (n = 29), endometrial cancer (n = 26), clear cell renal cell carcinoma (n = 22), bladder cancer (n = 18), melanoma (n = 17), pancreatic cancer (n = 14), thyroid cancer (n = 12), low-grade glioma (n = 12), sarcoma (n = 10), tumor of unknown origin (n = 8), meningioma (n = 7), prostate cancer (n = 7), gastrointestinal stromal tumor (n = 7), endocrine tumor (n = 6), gastric cancer (n = 5), head and neck squamous cell carcinoma (n = 4), kidney cancer (n = 3), brain cancer (n = 3), small cell lung cancer (n = 3), biliary cancer (n = 3), cervical cancer (n = 3), esophageal cancer (n = 3), oropharyngeal cancer (n = 2), liver cancer (n = 2), head and neck cancer (n = 2), mesothelioma (n = 2), and adrenal cancer (n = 1). Concordance in hotspot and non-hotspot regions were identified, and positive and negative percent agreements (PPA, NPA) for each type of variant between the 2 assays were used to assess the accuracy of xT CDx. Findings showed that 148 variants reported as somatic through the OM were detected as germline by xT CDx. A hotspot concordance analysis with the OM examined variants reported in hotspot regions that overlapped with OM targeted regions. Of the 416 samples, 164 featured at least 1 reported variant in an overlapping hotspot region, and 214 base pairs intersected at the defined hotspot regions of both the xT CDx and OM targeted regions. Investigators assessed 192 reported variants in hotspots from both assays, including 187 substitutions across 10 genes and 5 INDELs spanning 4 genes. They calculated the PPA and NPA for substitutions and INDELS in hotspot regions through the total variant counts of each classification across tumor samples to assess the accuracy of xT CDx. Among the 69 CRC samples tested with the OM, the detection of specific KRAS and NRAS CDx variants was examined. Among 31 CDx variants identified through OM, 31 were also detected by xT CDx, resulting in a PPA of 100% (95% CI, 88.8%-100.0%). Additionally, 649 variants were negative by the OM, and 648 were negative by xT CDx, leading to a NPA of 99.8% (95% CI, 99.1%-100.0%). References FDA grants breakthrough device designation to Tempus’ HLA-LOH companion diagnostic test. News release. Tempus. August 15, 2023. Accessed August 16, 2023. https://www.tempus.com/news/fda-grants-breakthrough-device-designation-to-tempus-hla-loh-companion-diagnostic-test/ Tempus receives US FDA approval of xT CDx, a NGS-based in vitro diagnostic device. News release. Tempus. May 1, 2023. Accessed August 16, 2023. https://www.tempus.com/news/tempus-receives-u-s-fda-approval-for-xt-cdx-a-ngs-based-in-vitro-diagnostic-device/ xT CDx: Technical information. Tempus Labs, Inc. February 2023. Accessed August 16, 2023. https://www.tempus.com/wp-content/uploads/2023/05/Tempus-xT-CDx_Technical-Information.pdf

Cancer Council NSW November marks Pancreatic Cancer Awareness Month. In recognition of this month, here are six things you should know about pancreatic cancer. 1. What is pancreatic cancer? Pancreatic cancer is cancer that starts in any part of the pancreas. About 70% of pancreatic cancers are found in the head of the pancreas. Pancreatic cancer can spread to nearby lymph nodes and to the lining of the abdomen (peritoneum). Cancer cells may also travel through the bloodstream to other parts of the body, such as the liver. 2. Who gets pancreatic cancer? About 4260 Australians are diagnosed with pancreatic cancer each year. More than 80% are over the age of 60. Pancreatic cancer was estimated to be the eighth most common cancer in Australia in 2021. A person has a 1 in 69 chance of being diagnosed with pancreatic cancer by the age of 85. 3. Types of pancreatic cancer There are two main types of pancreatic cancer. Exocrine tumours: These make up more than 95% of pancreatic cancers. The most common type is adenocarcinoma which begins in the lining of the pancreatic duct. 4. Risk factors for pancreatic cancer Risk factors that can increase a person’s chances of developing pancreatic cancer include: smoking tobacco (smokers are about twice as likely to develop pancreatic cancer as nonsmokers) obesity ageing eating too much red and processed meat drinking too much alcohol long-term diabetes (but diabetes can also be caused by the pancreatic cancer) long-term pancreatitis (inflammation of the pancreas) certain types of cysts in the pancreatic duct known as intraductal papillary mucinous neoplasms (IPMNs) – these should be assessed by an appropriate specialist stomach infections caused by the Helicobacter pylori bacteria (which can also cause stomach ulcers) family history and inherited conditions workplace exposure to certain pesticides, dyes or chemicals. Having risk factors does not mean you will definitely get cancer, but talk to your doctor if you are concerned. Some people with pancreatic cancer have no known risk factors. Screening tests help detect cancer in people who do not have any symptoms. Although there are useful screening tests for certain types of cancer, such as breast cancer and bowel cancer, there is currently no screening test available for pancreatic cancer. 5. Symptoms of pancreatic cancer In its early stages, pancreatic cancer rarely causes symptoms. Symptoms may not appear until the cancer is large enough to affect nearby organs or has spread. Common symptoms are: appetite loss nausea with or without vomiting unexplained weight loss pain in the upper abdomen, side or back, which may cause you to wake up at night changed bowel motions – including diarrhoea, severe constipation, or pale, oily, foul-smelling stools (poo) that are difficult to flush away newly diagnosed diabetes fatigue (feeling very tired). Some pancreatic NETs will also cause symptoms such as blurred vision, too much sugar in the blood or a drop in blood sugar, excessive thirst, increased urination and reflux. These symptoms can also occur in other conditions so speak to your doctor if you have any of these symptoms. Learn more about pancreatic cancer symptoms. 6. Diagnosing pancreatic cancer Tests to diagnose pancreatic cancer may include blood tests, imaging scans, and tissue sampling (biopsy). The tests you have will depend on the symptoms, type and stage of pancreatic cancer. Test results will show what type of pancreatic cancer it is, where in the pancreas it is, and whether it has spread outside the pancreas. Learn more about diagnosing pancreatic cancer. /Public Release. This material from the originating organization/author(s) might be of the point-in-time nature, and edited for clarity, style and length. Mirage.News does not take institutional positions or sides, and all views, positions, and conclusions expressed herein are solely those of the author(s).View in full here.

Eric Jonasch, MD Treatment with belzutifan (Welireg) led to a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with everolimus (Afinitor) in adult patients with advanced renal cell carcinoma (RCC) whose disease progressed following PD-1/PD-L1 and VEGF tyrosine kinase inhibitor (TKI) treatments, according to a press release.1 The primary end point of the phase 3 LITESPARK-005 study (NCT04195750) was met with this result, and the study also met a key secondary end point with belzutifan demonstrating significant improvement in overall response rate (ORR) compared with everolimus. Although not statistically significant, belzutifan also showed a trend toward improvement in overall survival (OS) vs everolimus. Results come from the prespecified interim analysis of LITESPARK-005. The safety portion of the analysis showed that belzutifan’s profile was consistent with that shown in prior studies. Full results will be presented at an upcoming medical meeting and shared with regulatory bodies. “Based on the data in patients with von Hippel-Lindau [VHL] disease, and on the phase 1b/2 study we conducted in patients with previously treated advanced RCC, it became clear belzutifan is an active drug,” Eric Jonasch, MD, professor in the department of genitourinary medical oncology, division of cancer medicine, at The University of Texas MD Anderson Cancer Center in Houston, TX, told Targeted Oncology™. “This registrational study, where patients with treatment-refractory clear cell RCC were randomized between belzutifan and everolimus, was conducted with the goal of obtaining approval for belzutifan in the refractory disease setting.” cancer cell | Image Credit: © catalin – www.stock.adobe.com The data rationalizing the exploration of belzutifan in previously treated advanced RCC were from LITESPARK-004 (NCT03401788). According to findings presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, belzutifan achieved anti-tumor activity and consistent safety in patient with VHL-related neoplasms. Of the 61 patients in the study, 83% had hemangioblastoma, and 33% had pancreatic neuroendocrine tumors (pNETs).2 The ORR in the hemangioblastoma cohort was 59% with a complete response (CR) rate of 3% and a partial response (PR) rate of 56%. The median duration of response (DOR) observed with belzutifan in the VHL population was not reached (range, 8.3+ to 27.6+ months). For the pNETs cohort, the ORR was 90%, with CRs in 3 patients and PRs in 15. The median DOR was not reached (range, 11.0+ to 31.0+ months). Sixteen percent of patients in the LITESPARK-004 study experienced grade 3 treatment-related adverse events (TRAEs). The most common TRAE was anemia, which occurred in 10% of patients. There were no grade 4 or 5 TRAEs during the study. Two patients discontinued treatment due to a TRAE. LITESPARK-005 is an open-label, randomized, phase 3 study in which patients are randomly assigned to receive oral belzutifan at 120 mg once daily or oral everolimus at 10 mg once daily. In addition to PFS, the study explores a coprimary end point of OS, and secondary end points other than ORR include DOR, the number of patients with adverse events, treatment discontinuation rate, and quality of life (QOL). QOL will be determined by several measure including time to deterioration (TTD) in health-related QOL, TTD in physical functioning, TTD in disease symptoms, change from baseline in health-related QOL, change from baseline in physical functioning, and change from baseline in European Quality of Life 5 Dimensions.3 The trial aims to enroll 746 patients with previously treated advanced RCC who meet the criteria. For inclusion, patients must have evidence of unresectable, locally advanced, metastatic disease, must have had disease progression on or after systemic therapy with a PD-1/PD-L1 inhibitor, must have received 3 prior systemic regimens for locally advanced or metastatic RCC, and have adequate organ function. All patients are required to use contraception once on the study, and female patients cannot be pregnant prior to starting therapy. “Patients with advanced RCC face low survival rates, and for those whose cancer progresses following PD-1/L1 and VEGF-TKI therapies, there is a need for new treatment options that can reduce their risk of disease progression or death,” said Marjorie Green, MD, senior vice president and head of late-stage oncology, global clinical development at Merck Research Laboratories, in a press release.1 “This is the first phase 3 trial to show positive results in advanced RCC following these therapies and the first new mechanism to demonstrate potential in advanced RCC in recent years. We look forward to discussing these results with health authorities.” “If these data lead to the approval of belzutifan for the treatment of refractory RCC, it provides patients and practitioners with an active, well-tolerated treatment option when patients progress on prior lines of therapy. The [AE] profile, with anemia, fatigue and hypoxemia being most common AEs, is easily manageable, making it an attractive choice,” said Jonasch. REFERENCES: 1. Merck Announces Welireg® (belzutifan) phase 3 LITESPARK-005 trial met primary endpoint of progression-free survival in certain previously treated patients with advanced renal cell carcinoma. News release. Merck, August 18, 2023. Accessed August 18, 2023. https://tinyurl.com/5duv497t 2. Jonasch E, Iliopolous O, Rathmell WK, et al. LITESPARK-004 (MK-6482-004) phase 2 study of belzutifan, an oral hypoxia-inducible factor 2α inhibitor (HIF-2α), for von Hippel-Lindau (VHL) disease: Update with more than two years of follow-up data. J Clin Oncol. 2022;40(suppl 16):4546. doi:10.1200/JCO.2022.40.16_suppl.4546 3. A study of belzutifan (MK-6482) versus everolimus in participants with advanced renal cell carcinoma (MK-6482-005). ClinicalTrials.gov. Updated August 1, 2022. Accessed August 18, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT04195750

Francois Lemonnier, MD, PhD Second-line treatment with axicabtagene ciloleucel (axi-cel; Yescarta) led to an investigator-assessed, 3-month complete metabolic response (CMR) rate of 71.0% (95% CI, 58.05%-81.80%) in patients with large B-cell lymphoma who were ineligible for autologous stem cell transplant (ASCT), according to data from the final analysis of the phase 2 ALYCANTE trial (NCT04531046). Findings presented at the 2023 EHA Congress showed that evaluable patients (n = 62) experienced a 3-month objective response rate (ORR) of 75.8%, including a partial response (PR) rate of 4.8%, per investigator assessment. No patients had stable disease (SD), 11.3% of patients had progressive disease, and 12.9% of patients were not evaluated. Notably, 59.7% of patients remained in CMR at 6 months. Per investigator assessment of best response, the ORR was 90.3%, including a CMR rate of 79.0%, a PR rate of 11.3%, and SD and progressive disease rates of 4.8% each. “The study met its primary end point with a CMR [rate] of 71% at 3 months vs a 12% expected [CMR rate] with historical controls,” presenting study author Francois Lemonnier, MD, PhD, of the Lymphoid Malignancies Unit at Henri-Mondor University Hospital in Créteil, France, said. The single-arm, open-label, multicenter trial conducted at 20 centers in France enrolled patients with aggressive B-cell non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma (HGBCL), and grade 3B follicular lymphoma, who were relapsed or refractory within 12 months of first-line chemoimmunotherapy. Patients needed to be ineligible for ASCT per physician assessment and at least 1 of the following: At least 65 years of age At least 18 years of age with a Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) score of at least 3 At least 18 years of age and underwent prior ASCT as first-line consolidation Other key inclusion criteria included an ECOG performance status of 0 to 2, adequate vascular access for leukapheresis, an absolute neutrophil count of at least 1 G/L, a platelet count of at least 75 G/L, an absolute lymphocyte count of at least 0.1 G/L, creatinine clearance of at least 40 mL/min, serum alanine transaminase/aspartate transaminase of no more than 2.5 times the upper limit of normal (ULN), a total bilirubin of no more than 26 µmol/L (unless a patient had Gilbert’s syndrome), a left ventricular ejection fraction of at least 45%, and a baseline oxygen saturation of at least 92% on room air. Following leukapheresis, bridging therapy with 1 or 2 cycles of R-GEMOX or corticosteroids was optional. After patients underwent lymphodepleting chemotherapy with 30 mg/m2 of fludarabine per day plus 500 mg/m2 of cyclophosphamide per day for 3 days, they received a single infusion of axi-cel. Patients underwent a PET scan and circulating tumor DNA (ctDNA) analysis on day 14 and at months 1, 3, 6, 9, and 12. Patients were enrolled between April 26, 2021, and June 15, 2022, and the data cutoff for the final analysis was January 19, 2023. The median follow-up was 12 months (range, 2.1-17.9). Investigator-assessed 3-month CMR rate was the primary end point. Secondary end points included 3-month CMR rate per independent review committee (IRC) assessment, event-free survival (EFS), duration of response, progression-free survival (PFS), overall survival (OS), safety, and health-related quality of life. The median age for patients treated with axi-cel was 70 years (range, 49-81), and 53.2% of patients were at least 70 years of age. Additionally, 75.8% of patients were male, 3.2% of patients underwent prior ASCT, and 32.3% of patients had a HCT-CI score of at least 3. The majority of patients had an ECOG performance status of 0 or 1 (98.4%), an International Prognostic Index score of 2 or higher (88.8%), Ann Arbor stage III or IV disease (74.2%), and were refractory to their first line of therapy (54.8%). Furthermore, 11.3% of patients had lactate dehydrogenase of at least the ULN at baseline, and 19.4% had a C-reactive protein serum level of more than 30 mg/L at infusion. Regarding histology, 83.9% of patients had DLBCL, 9.7% had HGBCL with MYC and BCL2 rearrangements with or without BCL6 rearrangements, 1.6% had follicular lymphoma with possible transformation to DLBCL not otherwise specified, 1.6% had grade 3B follicular lymphoma, and 3.2% had grade 1, 2, or 3A follicular lymphoma. Additionally, 83.9% of patients underwent bridging therapy. Among these patients, 98.1% received R-GEMOX, and 17.3% were given corticosteroids. The best response to bridging therapy included CMR (7.7%), partial metabolic response (26.9%), no response/stable disease (26.9%), progressive metabolic disease (36.5%), and not evaluated (1.9%). The median time between inclusion and axi-cel infusion was 41.5 days (min, 21; max, 71). A total of 69 patients underwent leukapheresis, and 7 patients were not infused with axi-cel due to death (n = 1), cutaneous nocardiosis (n = 1), complete remission prior to the infusion of CAR T-cell therapy (n = 1), absence of documented relapsed on biopsy prior to axi-cel infusion (n = 1), withdrawal of consent (n = 1), progressive disease (n = 1), and receipt of an investigational medical product and second-line chemotherapy for progression (n = 1). Five patients infused with axi-cel died prior to month 3 due to adverse effects (AEs; n = 3) and lymphoma (n = 2). At data cutoff, 50 patients were still alive, and 7 more deaths were reported due to AEs (n = 3), lymphoma (n = 3), and unknown (n = 1). Additional data showed that per IRC assessment, the 3-month ORR was 69.4%, including CMR, PR, SD, and progressive disease rates of 66.1%, 3.2%, 1.6%, and 14.5%, respectively. Notably, 14.5% of patients were not evaluated for 3-month response. Regarding best response, the IRC ORR was 91.9%, including CMR, PR, SD, and progressive disease rates of 82.3%, 9.7%, 1.6%, and 6.5%. Lemonnier noted that 3-month CMR rates were similar across evaluated subgroups. At day 14 following axi-cel infusion, 61.1% of evaluable patients (n = 33/54) had a negative PET-CT, and 48.1% (n = 25/52) had undetectable ctDNA. The median EFS was 12.3 months, and the 12-month EFS rate was 51.2% (95% CI, 38.3%-62.8%).

Raajit K. Rampal, MD, PhD Individualized myelofibrosis treatment begins with correctly identifying a patient’s disease subtype and considering their symptoms, from which accurate decisions regarding the use of JAK inhibitors vs radiation vs hypomethylating agents (HMAs) can lead to spleen and symptom burden reductions, according to Raajit K. Rampal, MD, PhD. During an OncLive® State of the Science Summit™ on hematologic malignancies, Rampal and colleagues highlighted the role of JAK inhibitors in myelofibrosis; considerations for CAR T-cell therapy in follicular lymphoma (FL); efficacy and safety findings with asciminib (Scemblix) in chronic myeloid leukemia (CML); the future of BTK inhibitors in mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL); unmet needs in diffuse large B-cell lymphoma (DLBCL); and research on the horizon in lower-risk myelodysplastic syndrome (MDS). Rampal, who chaired the event, is the director of the Myeloproliferative Neoplasms Program and an associate attending physician at Memorial Sloan Kettering Cancer Center in New York, New York. Rampal was joined by his colleagues: Alexander P. Boardman, MD, assistant attending physician, Memorial Sloan Kettering Cancer Center Michael J. Mauro, MD, leader, Myeloproliferative Neoplasm Program, Leukemia Service, Memorial Sloan Kettering Cancer Center Prioty Islam, MD, MSc, assistant attending physician, Memorial Sloan Kettering Cancer Center Jennifer K. Lue, MD, clinical director, Lymphoma Service, Memorial Sloan Kettering Cancer Center Jan Philipp Bewersdorf, MD, hematology/oncology fellow, Memorial Sloan Kettering Cancer Center Below, Rampal, Boardman, Mauro, Islam, Lue, and Bewersdorf summarize the main messages from their presentations. Current and Emerging Treatments in Myelofibrosis Rampal: [Myelofibrosis] treatment depends on the issue. This is 1 of the major principles in treating [patients with] myelofibrosis. It’s not a monolithic entity. This disease has different manifestations, and we need to treat the manifestation that is causing the patient the major issue. [When] some patients [present with myelofibrosis], anemia is the major [symptom] they’re [experiencing], not spleen [issues]––nothing else, just anemia. For those patients, a JAK inhibitor may not necessarily be the right choice, but [treatments such as] erythropoiesis-stimulating agents [ESAs], danazol, corticosteroids, or even immunomodulatory agents may be an appropriate first-line choice. However, for patients with symptomatic splenomegaly or constitutional symptoms, JAK inhibitors have made their mark. Compared with [treatments such as] hydroxyurea, JAK inhibitors have superior efficacy, reducing both spleen size and symptom burden. We have 3 FDA-approved [JAK inhibitors] currently. For other manifestations of this disease, there are other [treatments] we can use. For patients with extramedullary hematopoiesis in the lungs or bones, radiation is appropriate. For patients who are early in their disease, sometimes pegylated interferon can be useful; some data support that. When patients progress to accelerated or blast-phase disease, HMAs are the backbone of therapy, usually in combination with other agents. CAR T-Cell Therapy in FL Boardman: CAR T-cell therapy is clearly active in relapsed/refractory FL, with high response rates, and is effective in patients with high-risk disease. Current data suggest that these remissions are durable but given [that FL is] an indolent lymphoma, we need more time to [confirm these data]. Adverse effects [AEs] [including] cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome are common and must be considered when weighing treatment options for patients, especially those who may be frailer. Lastly, the optimal timing of CAR T-cell therapy vs bispecific antibodies and other targeted agents will require further study. Current and Novel TKIs in CML Mauro: We might think of ponatinib [Iclusig] being favored [over asciminib] in patients with primary resistance [and] high transcript levels. For patients with compound mutations and pan cytopenias, neither drug may be successful. These can be challenges. Patients with a mixture of intolerance and resistance who have perhaps more preserved response or at least more residual response from prior therapy exposure may have a better AE experience and better long-term outcomes with asciminib, at least speculatively. The T315I [mutation] is up for grabs. [Either ponatinib or asciminib may effectively target this mutation] because [both drugs seem to have activity there], and we don’t have concerns about the differences in dosing [between] asciminib [and ponatinib]. Looking into the future, other drugs are under further study. Olverembatinib, which is approved In China, is the drug that is closest to ponatinib and is in trials in the United States [US] now. [Regarding] other agents, we have some trials at Memorial Sloan Kettering Cancer Center. The [phase 1] ELVN-001 trial [NCT05304377] is open, [investigating an] ATP-competitive inhibitor that’s probably [similar to] ponatinib in its activity but may be much safer. Some other second-line allosteric inhibitors, such as TERN-701, [will also be investigated in clinical trials]. [The evolution of TKIs in CML is] a good story. A growing number of patients with CML are surviving CML, so survivorship is another effort and project at Memorial Sloan Kettering Cancer Center. The number of patients living with CML in the US will probably be 10 times what it used to be by the middle of the century. Asciminib will be a big help, [because] it offers better safety [than other TKIs]. We’ll see how other trials look. BTK Inhibitors in CLL and MCL Islam: BTK inhibition with small-molecule–targeted drugs has transformed the way we treat [patients with] B-cell malignancies over the past decade, ever since the advent of ibrutinib [Imbruvica] in the early 2010s. Newer-generation BTK inhibitors continue to improve safety and efficacy and are now even trying to overcome the resistance mechanisms we’ve seen with covalent BTK inhibitors. These drugs are being studied as monotherapies and have promising efficacy as single agents. [They] are also being combined with already-approved and emerging therapies. This has been a paradigm shift in both CLL and MCL, away from combination chemoimmunotherapy and more intensive therapies like autologous stem cell transplantation, potentially. There’s much to come, and many exciting data will be published in the next couple of years. Updates in DLBCL Management Lue: POLA-R-CHP [rituximab (Rituxan), cyclophosphamide, doxorubicin, polatuzumab vedotin-piiq (Polivy), and prednisone], has become the standard of care [(SOC) for patients with DLBCL with an] International Prognostic Index [score of] 2 and activated B-cell biology. We

Prioty Islam, MD, MSc, attending physician, medical oncologist, Leukemia, Division of Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, discusses how the approval of the noncovalent BTK inhibitor pirtobrutinib (Jaypirca) has transformed the treatment of patients with mantle cell lymphoma (MCL), and where this agent fits in to the current treatment armamentarium. Pirtobrutinib received FDA approval in January, 2023, for the treatment of patients with relapsed/refractory MCL who have been previously exposed to at least 2 prior lines of systemic therapy, including a BTK inhibitor. This approval was supported by data from the phase 1/2 BRUIN trial (NCT03740529), in which a subset of patients with MCL achieved a high overall response rate (ORR) with the agent. Historically, patients with relapsed/refractory MCL experienced poor prognosis and did not respond well to chemoimmunotherapy regimens, Islam begins. However, the introduction of single-agent, oral targeted BTK inhibitors, such as pirtobrutinib, to the treatment armamentarium has improved the durability of patient responses to treatment, Islam states, as well as patients’ quality of life. Accordingly, this drug class has significantly affected the treatment of relapsed/refractory MCL, she says. Much like its activity in chronic lymphocytic leukemia, pirtobrutinib has been shown to successfully restore BTK inhibitor dependency in patients with MCL, as well as induce responses in those who previously progressed on a different BTK inhibitor, Islam continues. Although there is interest in moving pirtobrutinib into earlier lines of therapy in MCL, efforts to accomplish this remain both a challenge and a subject of debate due to a lack of data on patient responses after progression on pirtobrutinib, Islam cautions. The ongoing, randomized phase 3 BRUIN-MCL-321 trial (NCT04662255) is investigating pirtobrutinib vs investigator’s choice of BTK inhibitor in patients with pretreated, BTK inhibitor–naïve MCL. Findings from the trial are hoped to illuminate the feasibility of utilizing pirtobrutinib in the frontline, as the current FDA indication for this agent is after progression on or intolerance to a prior covalent BTK inhibitor, Islam says. Disclosures: Dr Islam reports consulting roles with AbbVie, AstraZeneca, BeiGene, DAVA Oncology, and LOXO Oncology; as well as speaking roles with Targeted Oncology and The Video Journal of Hematologic Oncology (VJHemOnc).

Avelumab in dMMR/MSI Metastatic CRC | Image Credit: © PIC4U – stock.adobe.com Patients with mismatch repair–deficient and/or microsatellite instability (dMMR/MSI) metastatic colorectal cancer (CRC) experienced a progression-free survival (PFS) benefit with longer disease control following treatment with avelumab (Bavencio) compared with standard second-line chemotherapy, according to findings from the phase 2 SAMCO-PRODIGE 54 trial (NCT03186326) published in JAMA Oncology. At a median follow-up of 33.3 months (95% CI, 28.3-34.8), patients who received the anti–PD-L1 monoclonal antibody (n = 61) experienced a median PFS of 4.1 months (range, 2.31-5.68) compared with 6.2 months (range, 4.11-7.29) among patients who received standard chemotherapy (n = 61). However, study authors noted that because the Kaplan-Meier curves crossed at 7.3 months corresponding to a PFS rate of 36%, the log-rank test and the hazard ratio of PFS analyses were not sufficient (log-rank P = .30). Using the Qiu and Sheng statistical test that appeared better suited for this analysis, investigators determined that avelumab was superior to chemotherapy in terms of PFS (P = .03); the estimated 12- and 18-month PFS rates were 31.2% (95% CI, 20.1%-42.9%) and 27.4% (95% CI, 16.8%-39.0%), respectively, in the avelumab arm compared with 19.4% (95% CI, 10.6%-30.2%) and 9.1% (95% CI, 3.2%- 18.8%), respectively, in the control arm. Additionally, the estimated restricted mean survival time for PFS was 12.3 months (95% CI, 8.7-15.8) vs 8.1 months (95% CI, 6.2-10.0) in the avelumab and chemotherapy arms, respectively, after 36 months of follow-up (P = .04). The overall response rates (ORR) were comparable with 29.5% of patients in the avelumab arm vs 26.2% in the chemotherapy arm experiencing a response. The disease control rate was 70.5% in the avelumab arm vs 77.0% in the chemotherapy arm, and among these patients the rate of ongoing disease control at 18 months was 75.7% vs 19.1%, respectively. The median duration of disease control was 16.7 months (interquartile range [IQR], 5.7-33.4) vs 7.3 months (IQR, 4.9-11.9), respectively (P < .001). SAMCO-PRODIGE 54 was an open-label trial that was conducted at 40 centers in France. To be included in the study, patients needed to be at least 18 years of age with unresectable dMMR/MSI stage IV CRC, a World Health Organization (WHO) performance status score of 1 or less, and adequate organ function. All patients experienced disease progression after receiving a first-line standard chemotherapy regimen with or without a targeted agent based on RAS status. Patients who were enrolled on the study were randomly assigned in a 1:1 manner to receiveavelumab at a dose of 10 mg/kg every 2 weeks intravenously or investigator’s choice of second-line chemotherapy. In the chemotherapy arm, patients were also allowed to receive a targeted agent according to first-line treatment regimen and RAS/BRAF status; if progression occurred, patients could receive an immune checkpoint inhibitor at the investigator’s discretion. Treatment proceeded until disease progression, unacceptable toxicity, or withdrawal. Stratification occurred by center, WHO performance status, BRAF status, and age. The primary end point was PFS by RECIST v1.1 criteria, and patients who were alive without progression were censored on the date of last news. Secondary end points included overall survival (OS), ORR, time to best response, duration of disease control, and safety. The baseline patient characteristics were well balanced between the avelumab and chemotherapy arms; the median age was 66 years (IQR, 54-75) and 67 years (IQR, 60-75), respectively. Most patients in both arms had right-sided primary tumors (87% vs 77%) and had previously received FOLFOX/CAPOX with or without targeted therapy (65.6% vs 70.5%). BRAF V600E (41% vs 44%) and RAS (23% vs 21%) mutations were present in patients in both arms. Additionally, patients had more than 5 metastases at rates of 41% in the avelumab arm vs 44% in the chemotherapy arm. Additional findings showed that patients in both the avelumab and chemotherapy arms experienced complete response (6.6% vs 4.9%), partial response (23.0% vs 21.3%), stable disease (41.0% vs 50.8%), and progressive disease (27.9% vs 16.4%). The time to best response was 3.5 months (IQR, 2.0-8.0) vs 2.0 months (IQR, 1.8-2.5), respectively. The median duration of treatment in the avelumab and chemotherapy arms was 7.4 months (range, 0.03-46.5) vs 5.1 months (range, 0.03-19.7), respectively, and the median OS was 25.8 months (95% CI, 14.1-not reported [NR]) vs 23.4 months (95% CI, 13.0-NR), respectively (HR, 0.94; 95% CI, 0.57- 1.53; P = .79). At the May 23, 2022, data cutoff, 32 patients in each arm had died. Most patients in the chemotherapy arm (50.8%) were subsequently treated with an immune checkpoint inhibitor. Overall, 83.8% of patients in the chemotherapy arm who received a subsequent line of therapy were treated with an immune checkpoint inhibitor. In the avelumab arm, 29.5% of patients were still being treated with the agent and 53.5% of patients who experienced disease progression received a subsequent anticancer therapy. In terms of safety, in the 63-patient avelumab arm and the 64-patient chemotherapy arm treatment-related adverse effects (TRAEs) of any grade occurred at rates of 88.9% vs 98.4%, respectively. TRAEs of grade 3 or 4 severity occurred at rates of 31.7% vs 53.1%, respectively, and included abnormal liver test results (7.9% vs 1.6%), diarrhea (4.8% vs 7.8%), neurotoxicity (1.6% vs 3.1%), and hypertension (1.6% vs 10.9%), among others. Grade 3 or 4 neutropenia was reported in 18.8% of patients in the chemotherapy arm. Immune-mediated AEs occurred in 17.5% of patients in the avelumab arm, including grade 1 to 2 hypothyroidism (n = 6), grade 1 to 2 hyperthyroidism (n = 5), grade 3 colitis (n = 1), grade 2 infusion-related reactions (n = 2), and a grade 3 infusion-related reaction (n = 1). In the chemotherapy arm, 3.1% of patients experienced cetuximab (Erbitux) infusion–related reactions. Six patients in the avelumab arm and 7 patients in the chemotherapy arm discontinued treatment due to an AE. No grade 5 AEs were reported in either arm. Reference Taïeb J, Bouche O, André T, et al. Avelumab vs standard second-line chemotherapy in patients with metastatic colorectal cancer and microsatellite instability: a randomized clinical trial. JAMA Oncol.

Appointment of industry veterans, Dr. Hans-Peter Gerber, PhD, as Chairman and Dr. Bernd Eschgfäller, PhD, as independent Board member. Strengthens T-CURX’s Board to accelerate the commercialization of its proprietary CAR-T technologies and CAR-T pipeline programs. WÜRZBURG, Germany, August 28, 2023 / B3C newswire / — T-CURX GmbH (“T-CURX” or the “Company”), a biopharmaceutical company focused on the development of next-generation CAR-T cell therapies for cancer patients, today announces the appointments of Dr. Hans-Peter (HP) Gerber, PhD, as Chairman and of Dr. Bernd Eschgfäller, PhD, as an independent Board member. Both appointments are effective immediately. The addition of these two high-profile industry experts will significantly bolster the network and the commercial expertise of T-CURX’s Board of Directors, which also includes representatives of T-CURX’s investors and co-founders. Dr. HP Gerber has a strong industry background with prior leadership and senior management positions at industry leading organizations including Genentech, Seattle Genetics (now Seagen) and Pfizer. More recently, he has been Chief Scientific Officer of a number of biotech companies, including MPM-backed Maverick Therapeutics, acquired by Takeda, and cell therapy company 3T Biosciences, where he was involved in the company’s $40 million Series A fundraising in 2022. HP also served as independent Board member of NBE-Therapeutics, where he was instrumental in the company’s successful acquisition by Boehringer Ingelheim. Dr. Bernd Eschgfäller is an industry-experienced cell therapy expert who joins T-CURX from Novartis, where most recently he was Head of Customer Operations, Cell & Gene Therapy Europe. In his 20+ year career, he has held leadership positions across operations, commercial and development at Novartis. Bernd is an internationally-recognized leader in the field of CAR-T therapy development and the commercialization of CAR- T cells. He co-led the design of the commercial model for cell therapies at Novartis and was an instrumental member of the European Cell & Gene Leadership Team responsible for the launch and commercialization of Kymriah®, the first FDA-approved CAR-T cell product. Dr. Ulf Grawunder, co-founder and Chief Executive Officer of T-CURX, commented: “I am excited to welcome HP and Bernd to T-CURX’s Board of Directors. Both are extremely well-connected, high-caliber industry veterans with a wealth of commercial and technical expertise in oncology, specifically in the development of cellular therapies. The appointment of these two high-profile industry veterans underlines the significant potential of T-CURX and its groundbreaking innovations in CAR-T development.” Dr. HP Gerber, Chairman of T-CURX, commented: “I am delighted to join T-CURX’s Board of Directors as its Chairman and work with the Company’s impressive team to leverage its CAR-T technologies and clinical pipeline. I am impressed with the quality of the science and technology that is being commercially translated at T-CURX by an outstanding, growing operational team built in a short period of time. I look forward to bringing the transformative innovations of T-CURX in the CAR-T cell space to many cancer patients in the future.” Dr. Bernd Eschgfäller, Board Member, commented: “I am thrilled to join the Board of T-CURX, to leverage my expertise in CAR-T cell development and commercialization to accelerate the Company’s future development. I have followed the innovative work of Prof. Michael Hudecek, T-CURX’s co-founder, for many years, and I am excited to help T-CURX’s talented team to commercially translate their excellent science and technology for the benefit of patients in need of improved therapies.” The appointments of Dr. Gerber and Dr. Eschgfäller follows the strengthening of T-CURX’s management team over the past year with the appointments of Dr. Ulf Grawunder as Chief Executive Officer in October 2022, Tom Loeser as Chief Financial Officer in December 2022, and Prof. Michael Hudecek as Chief Medical Officer and Dr. Karl Schumacher as Chief Clinical Officer in June 2023. About T-CURX T-CURX GmbH (“T-CURX”) is a private biopharmaceutical company focused on identifying, developing and commercialising next generation CAR-T cell therapies in cancer indications of high medical need. Based in Germany, the Company´s proprietary CAR-T technologies were developed in the labs of co-founder Professor Michael Hudecek at Universitätsklinikum Würzburg and are centered around a novel Sleeping Beauty (“SB”) Transposon gene transfer technology, which is exclusively licensed to T-CURX.T-CURX leverages several cutting-edge CAR-T engineering technologies, including virus-free transposon based genetic engineering and a highly flexible and modular CAR format. This provides unparalleled flexibility, efficacy, safety, but also scalability for developing CAR-T cells at significantly lower costs than conventional lentivirus-based CAR-T cell manufacturing. With an ambition to democratize transformative personalized CAR-T immunotherapies, T-CURX has a development pipeline of four CAR-T programmes. The Company’s first product is currently in Phase I clinical development whilst the second CAR-T programme, a novel target, is ready for a Clinical Trial Application (CTA). Contacts T-CURX GmbHUlf Grawunder, Chief Executive OfficerThis email address is being protected from spambots. You need JavaScript enabled to view it.+49-(0)-931-250-99-712 Media enquiries This email address is being protected from spambots. You need JavaScript enabled to view it. FTI Consulting (PR adviser to T-CURX)Simon Conway, Natalie Garland-Collins, Alex DavisThis email address is being protected from spambots. You need JavaScript enabled to view it.+44-(0)-20-3727-1000 Keywords: Leadership; Organization and Administration; Receptors, Chimeric Antigen; Immunotherapy; T-Lymphocytes; Genetic Engineering; Transposases; Neoplasms; Humans; Biotechnology; Germany Published by B3C newswire

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