On December 11, 2023 Johnson & Johnson reported an analysis from the Phase 1/2 MonumenTAL-1 study of TALVEY (talquetamab-tgvs) in patients with relapsed or refractory multiple myeloma (RRMM) showed that patients treated with TALVEY were subsequently treated effectively with several classes of therapy, including anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR-T) therapy as well as BCMA and anti-Fc receptor-like protein 5 (FcRH5) bispecific antibodies, after TALVEY treatment (Press release, Johnson & Johnson, DEC 11, 2023, View Source [SID1234638450]). These data, featured in a poster presentation at the 2023 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Abstract #2007), highlight the versatility of TALVEY when used before or after BCMA-directed CAR-T and bispecifics in triple-class exposed patients with RRMM.1 Additional results from the MonumenTAL-1 study, also featured in a poster presentation, support the overall versatility of TALVEY by showing continued strong efficacy among patients with prior exposure to T-cell redirection therapy (TCR) (Abstract #3377).2

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

In MonumenTAL-1, 297 patients with no prior exposure to TCR received TALVEY at the recommended Phase 2 dose (RP2D) of 0.8 mg/kg biweekly (Q2W) [n=154] or 0.4 mg/kg weekly (QW) [n=143].1 Patients in the study received a median of five prior lines of therapy; 75 percent of patients were triple-class refractory; 29 percent were penta-drug refractory; and 12 percent had prior belantamab mafodotin exposure.1 Overall, 162 patients received at least one subsequent antimyeloma therapy (SAT) after TALVEY discontinuation, including chemotherapy-based regimens (n=48); a proteasome inhibitor- (PI), an immunomodulatory drug- (IMiD), or other anti-neoplastic–containing regimen (n=44); anti-CD38 mAb-containing regimens (n=27); bispecific antibodies (n=23; n=19 anti–BCMA; n=4 anti–FcRH5); CAR-T therapy (n=17; including n=9 anti–BCMA-targeting CAR-T); or anti-BCMA antibody-drug conjugates (n=9).1

Results show that patients who discontinued TALVEY were able to achieve a response with SATs, including 65 percent (11/17) of patients who received subsequent CAR-T cell therapy, of whom 35 percent achieved a complete response (CR) or better.1 Patients treated with anti-BCMA bispecific antibodies as the first SAT achieved an overall response rate (ORR) of 58 percent (11/19), and 75 percent (3/4) responded to anti-FcRH5 bispecific antibody therapy as the first SAT.1

A separate updated analysis of the MonumenTAL-1 study, focused on safety and efficacy of TALVEY in patients with RRMM after prior TCRs (n=70), showed continued strong efficacy of TALVEY across populations exposed to TCR (predominantly anti-BCMA), with an ORR of 73 percent and median duration of response (mDOR) of more than 1 year in the post–CAR-T cell therapy setting.2 More than 56 percent of patients exposed to prior bispecific antibody responded.2

"Results from the MonumenTAL-1 analyses support the versatility of talquetamab either before or after BCMA-directed CAR-T and bispecifics in patients with triple-class exposed relapsed or refractory multiple myeloma," said Ajai Chari, M.D., Director of Multiple Myeloma Program, Professor of Clinical Medicine at the University of California, San Francisco.‡ "Talquetamab presents a new treatment option for patients and physicians who want to save BCMA-directed for later lines of therapy."

Data from the Pivotal Phase 1/2 MonumenTAL-1 Study Highlight Reported Continued Efficacy of TALVEY with Reduced Intensity Dosing

An oral presentation at ASH (Free ASH Whitepaper) 2023 highlighted results from 50 patients in the Phase 1/2 MonumenTAL-1 study who were switched to reduced intensity dosing based on meeting specific response criteria or to mitigate treatment-emergent adverse events (TEAEs) such as oral-, nail- and/or skin-related TEAEs, which may be related to expression of GPRC5D (Abstract #1010).3 Patients whose dose was reduced maintained durable responses to TALVEY treatment.3 Two additional cohorts, which were conducted to examine the impact of prospective reduction in dosing intensity after response was achieved, included 24 patients with a median follow-up of 13.2 months.3 In total, 79 percent (19/24) of patients achieved a partial response (PR) or better and switched from 0.8 mg/kg Q2W to either 0.4 mg/kg Q2W or 0.8 mg/kg Q4W.3 Following the change in dosing, at six months, mDOR was not reached.3

Patients who prospectively switched to reduced dosing intensity trended towards improved resolution of GPRC5D-related TEAEs, except for weight loss (prospective: 12.5 percent resolved and without dose reduction: 18.9 percent resolved).3 Resolution of TEAEs occurred for oral-toxicities (33.3 percent and 26.9 percent); nail-toxicities (11.1 percent and 12.0 percent) and non-rash skin-toxicities (50.0 percent and 15.3 percent), in the prospective and without dose reduction cohorts, respectivly.3 Thus, improvement or resolution of oral-, nail-, and skin-related TEAEs was observed over time in some patients in the prospective reduced and less frequent dosing cohorts.3

These results show the potential of modifying the TALVEY dose, after a response is achieved, as a strategy to manage oral-, nail-, and skin-related TEAEs and improve patient experience without compromising efficacy.3

First-ever Results from Study of TALVEY and IMiD Combination Show Promising Overall Response Rate in Patients with RRMM

Results from the Phase 1b MonumenTAL-2 study of TALVEY and pomalidomide for the treatment of patients with RRMM highlight the potential to combine TALVEY with other anti-myeloma therapies.4 These data, from the first-ever study of a regimen combining a GPRC5D-targeted therapy and an immunomodulatory agent, were featured as an oral presentation at the 2023 ASH (Free ASH Whitepaper) Annual Meeting (Abstract #1014).4

Patients in the Phase 1b MonumenTAL-2 study (n=35) were treated with subcutaneous (SC) TALVEY at the RP2D of 0.8 mg/kg Q2W (n=19) or 0.4 mg/kg QW (n=16) with step-up doses, plus two milligrams of oral pomalidomide daily.4 With a median follow-up of 15 months in the QW cohort (n=16), the overall response rate was 94 percent among response-evaluable patients, 63 percent achieved a CR or better, and 88 percent of responders achieved a very good partial response (VGPR) or better.4 With a median follow-up of 11.1 months in the Q2W cohort (n=19), the ORR was 84 percent in response-evaluable patients, with 37 percent achieving a CR or better and 68 percent achieving a VGPR or better.4 Overall response rates were consistent across patient subgroups, including patients treated with prior pomalidomide or CAR-T cell therapy.4

Responses in both patient cohorts were rapid, with a median time to first response of 1.7 months (range, 0.9–3.3) in the QW cohort and 1.2 months (range, 0–4.8) in the Q2W cohort.4 At nine months, 100 percent of responders maintained their response in the QW cohort and 84 percent maintained response in the Q2W cohort.4 mDOR and progression-free survival (PFS) were not reached, and 9-month PFS rates observed in the QW and Q2W cohorts were 94 percent and 76 percent, respectively.4

"Findings from the MonumenTAL-2 and MonumenTAL-1 studies demonstrate the versatility of TALVEY across patient subgroups, showing the efficacy, manageable safety profile and effect of TALVEY on B-cell preservation," said Christoph Heuck, M.D., Vice President, Hematology Clinical Development, Johnson & Johnson Innovative Medicine. "The promising early results observed with the combination of TALVEY and pomalidomide, even in patients who had previously received pomalidomide or CAR-T cell therapy, reinforce our scientific strategy in focusing on improving upon and deepening responses through combination regimens."

The most common adverse events across both cohorts were oral related (86 percent); cytokine release syndrome (CRS; 74 percent; 3 percent Grade 3/4); neutropenia (63 percent).4 Most common grade 3/4 hematologic AEs were neutropenia (54 percent), anemia (26 percent), and thrombocytopenia (20 percent).4 Nail, skin, and rash toxicities occurred in 69 percent, 74 percent, and 20 percent of patients, respectively; the majority were Grade 1/2 with no discontinuations.4 Grade 1 immune effector cell-associated neurotoxicity syndrome occurred in three patients.4 Infections occurred in 80 percent of patients (23 percent Grade 3/4); most common were pneumonia (23 percent) and upper respiratory tract infection (23 percent).4 Adverse events led to TALVEY dose reduction or schedule change in 34 percent of patients and dose reduction of pomalidomide in 46 percent of patients.4 In total, four patients discontinued treatment. One patient died due to pulmonary embolism.4

About TALVEY
TALVEY (talquetamab-tgvs) received approval from the U.S. FDA in August 2023 as a first-in-class GPRC5D-targeting bispecific antibody for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody.5 The European Commission (EC) granted conditional marketing authorization (CMA) of TALVEY ▼ (talquetamab) in August 2023 as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma (RRMM) who have received at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody and have demonstrated disease progression on the last therapy.6

TALVEY is a bispecific T-cell engaging antibody that binds to the CD3 receptor expressed on the surface of T-cells and G protein-coupled receptor class C group 5 member D (GPRC5D), a novel multiple myeloma target which is highly expressed on the surface of multiple myeloma cells and non-malignant plasma cells, as well as some healthy tissues such as epithelial cells of the skin and tongue.

For more information, visit www.TALVEY.com.

About MonumenTAL-1

MonumenTAL-1 (Phase 1: NCT03399799, Phase 2: NCT04634552) is a Phase 1/2 single-arm, open-label, multicohort, multicenter dose-escalation study involving more than 300 patients.7,8 Phase 1 evaluated the safety and efficacy of TALVEY in adults with relapsed or refractory multiple myeloma who received three or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.1,2 The study excluded patients who experienced T-cell redirection therapy within 3 months, prior Grade 3 or higher CRS related to any T-cell redirection therapy, an autologous stem cell transplant within the 12 weeks, an allogenic stem cell transplant within the 6 months, Eastern Cooperative Oncology Group (ECOG) performance score of 3 or higher, stroke or seizure within 6 months, CNS involvement or clinical signs of meningeal involvement of multiple myeloma, plasma cell leukemia, or active or documented history of autoimmune disease (exception of vitiligo, resolved childhood atopic dermatitis or resolved Grave’s Disease that is euthyroid based on clinical and laboratory testing).7,8

Phase 2 of the study evaluated the efficacy of TALVEY in participants with relapsed or refractory multiple myeloma at the recommended Phase 2 dose(s) (RP2Ds), established as SC 0.4 mg/kg weekly and 0.8 mg/kg every two weeks, respectively. Efficacy was based on overall response rate (ORR) and duration of response (DOR) as assessed by an Independent Review Committee using the International Myeloma Working Group (IMWG) criteria.3

About MonumenTAL-2

The MonumenTAL-2 (NCT05050097) study is an ongoing Phase 1 study of subcutaneous talquetamab in combination with carfilzomib, daratumumab SC, lenalidomide or pomalidomide for the treatment of patients with multiple myeloma. The primary objective of the MonumenTAL-2 study is to identify and characterize the safety of the treatment combinations. Secondary objectives of the MonumenTAL-2 study include overall response rates, duration of response and time to response.

About Multiple Myeloma
Multiple myeloma is an incurable blood cancer that affects a type of white blood cell called plasma cells, which are found in the bone marrow.9 In multiple myeloma, these plasma cells change, spread rapidly and replace normal cells in the bone marrow with tumors.10 Multiple myeloma is the third most common blood cancer and remains an incurable disease.11 In 2023, it is estimated that more than 35,000 people will be diagnosed with multiple myeloma in the U.S. and more than 12,000 people will die from the disease.12 People living with multiple myeloma have a five-year relative survival rate of 59.8 percent.13 While some people diagnosed with multiple myeloma initially have no symptoms, most patients are diagnosed due to symptoms that can include bone fracture or pain, low red blood cell counts, tiredness, high calcium levels and kidney problems or infections.14,15

TALVEY IMPORTANT SAFETY INFORMATION

INDICATION AND USAGE

TALVEY (talquetamab-tgvs) is indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

This indication is approved under accelerated approval based on response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

IMPORTANT SAFETY INFORMATION

WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITY, including IMMUNE EFFECTOR CELL-ASSOCIATED NEUROTOXICITY SYNDROME

Cytokine release syndrome (CRS), including life-threatening or fatal reactions, can occur in patients receiving TALVEY. Initiate TALVEY treatment with step-up dosing to reduce the risk of CRS. Withhold TALVEY until CRS resolves or permanently discontinue based on severity.

Neurologic toxicity, including immune effector cell-associated neurotoxicity syndrome (ICANS), and serious and life-threatening or fatal reactions, can occur with TALVEY. Monitor patients for signs and symptoms of neurologic toxicity including ICANS during treatment. Withhold or discontinue TALVEY based on severity.

Because of the risk of CRS and neurologic toxicity, including ICANS, TALVEY is available only through a restricted program called the TECVAYLI and TALVEY Risk Evaluation and Mitigation Strategy (REMS).

CONTRAINDICATIONS: None.

WARNINGS AND PRECAUTIONS

Cytokine Release Syndrome (CRS): TALVEY can cause cytokine release syndrome, including life-threatening or fatal reactions. In the clinical trial, CRS occurred in 76% of patients who received TALVEY at the recommended dosages, with Grade 1 CRS occurring in 57% of patients, Grade 2 in 17%, and Grade 3 in 1.5%. Recurrent CRS occurred in 30% of patients. CRS occurred in 33% of patients with step-up dose 3 in the biweekly dosing schedule (N=153). CRS occurred in 30% of patients with the first 0.4 mg/kg treatment dose and in 12% of patients treated with the first 0.8 mg/kg treatment dose. The CRS rate for both dosing schedules combined was less than 3% for each of the remaining doses in Cycle 1 and less than 3% cumulatively from Cycle 2 onward. The median time to onset of CRS was 27 (range: 0.1 to 167) hours from the last dose, and the median duration was 17 (range: 0 to 622) hours. Clinical signs and symptoms of CRS include but are not limited to pyrexia, hypotension, chills, hypoxia, headache, and tachycardia. Potentially life-threatening complications of CRS may include cardiac dysfunction, acute respiratory distress syndrome, neurologic toxicity, renal and/or hepatic failure, and disseminated intravascular coagulation (DIC).

Initiate therapy with step-up dosing and administer pre-treatment medications (corticosteroids, antihistamine, and antipyretics) prior to each dose of TALVEY in the step-up dosing schedule to reduce the risk of CRS. Monitor patients following administration accordingly. In patients who experience CRS, pre-treatment medications should be administered prior to the next TALVEY dose.

Counsel patients to seek medical attention should signs or symptoms of CRS occur. At the first sign of CRS, immediately evaluate patient for hospitalization and institute treatment with supportive care based on severity, and consider further management per current practice guidelines. Withhold TALVEY until CRS resolves or permanently discontinue based on severity.

Neurologic Toxicity including ICANS: TALVEY can cause serious or life-threatening neurologic toxicity, including immune effector cell-associated neurotoxicity syndrome (ICANS), including fatal reactions. In the clinical trial, neurologic toxicity occurred in 55% of patients who received the recommended dosages, with Grade 3 or 4 neurologic toxicity occurring in 6% of patients. The most frequent neurologic toxicities were headache (20%), encephalopathy (15%), sensory neuropathy (14%), and motor dysfunction (10%).

ICANS was reported in 9% of 265 patients where ICANS was collected and who received the recommended dosages. Recurrent ICANS occurred in 3% of patients. Most patients experienced ICANS following step-up dose 1 (3%), step-up dose 2 (3%), step-up dose 3 of the biweekly dosing schedule (1.8%), or the initial treatment dose of the weekly dosing schedule (2.6%) (N=156) or the biweekly dosing schedule (3.7%) (N=109). The median time to onset of ICANS was 2.5 (range: 1 to 16) days after the most recent dose with a median duration of 2 (range: 1 to 22) days. The onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of CRS. Clinical signs and symptoms of ICANS may include but are not limited to confusional state, depressed level of consciousness, disorientation, somnolence, lethargy, and bradyphrenia.

Monitor patients for signs and symptoms of neurologic toxicity during treatment. At the first sign of neurologic toxicity, including ICANS, immediately evaluate the patient and provide supportive care based on severity; withhold or permanently discontinue TALVEY based on severity and consider further management per current practice guidelines. [see Dosage and Administration (2.5)].

Due to the potential for neurologic toxicity, patients receiving TALVEY are at risk of depressed level of consciousness. Advise patients to refrain from driving or operating heavy or potentially dangerous machinery during the step-up dosing schedule and for 48 hours after completion of the step-up dosing schedule, and in the event of new onset of any neurological symptoms, until symptoms resolve.

TECVAYLI and TALVEY REMS: TALVEY is available only through a restricted program under a REMS, called the TECVAYLI and TALVEY REMS because of the risks of CRS and neurologic toxicity, including ICANS.

Further information about the TECVAYLI and TALVEY REMS program is available at www.TEC-TALREMS.com or by telephone at 1-855-810-8064.

Oral Toxicity and Weight Loss: TALVEY can cause oral toxicities, including dysgeusia, dry mouth, dysphagia, and stomatitis. In the clinical trial, 80% of patients had oral toxicity, with Grade 3 occurring in 2.1% of patients who received the recommended dosages. The most frequent oral toxicities were dysgeusia (49%), dry mouth (34%), dysphagia (23%), and ageusia (18%). The median time to onset of oral toxicity was 15 (range: 1 to 634) days, and the median time to resolution to baseline was 43 (1 to 530) days. Oral toxicity did not resolve to baseline in 65% of patients.

TALVEY can cause weight loss. In the clinical trial, 62% of patients experienced weight loss of 5% or greater, regardless of having an oral toxicity, including 28% of patients with Grade 2 (10% or greater) weight loss and 2.7% of patients with Grade 3 (20% or greater) weight loss. The median time to onset of Grade 2 or higher weight loss was 67 (range: 6 to 407) days, and the median time to resolution was 50 (range: 1 to 403) days. Weight loss did not resolve in 57% of patients who reported weight loss.

Monitor patients for signs and symptoms of oral toxicity. Counsel patients to seek medical attention should signs or symptoms of oral toxicity occur and provide supportive care as per current clinical practice, including consultation with a nutritionist. Monitor weight regularly during therapy. Evaluate clinically significant weight loss further. Withhold TALVEY or permanently discontinue based on severity.

Infections: TALVEY can cause infections, including life-threatening or fatal infections. Serious infections occurred in 16% of patients, with fatal infections in 1.5% of patients. Grade 3 or 4 infections occurred in 17% of patients. The most common serious infections reported were bacterial infection (8%), which included sepsis and COVID-19 (2.7%).

Monitor patients for signs and symptoms of infection prior to and during treatment with TALVEY and treat appropriately. Administer prophylactic antimicrobials according to local guidelines. Withhold or consider permanently discontinue TALVEY as recommended, based on severity.

Cytopenias: TALVEY can cause cytopenias, including neutropenia and thrombocytopenia. In the clinical trial, Grade 3 or 4 decreased neutrophils occurred in 35% of patients, and Grade 3 or 4 decreased platelets occurred in 22% of patients who received TALVEY. The median time to onset for Grade 3 or 4 neutropenia was 22 (range: 1 to 312) days, and the median time to resolution to Grade 2 or lower was 8 (range: 1 to 79) days. The median time to onset for Grade 3 or 4 thrombocytopenia was 12 (range: 2 to 183) days, and the median time to resolution to Grade 2 or lower was 10 (range: 1 to 64) days. Monitor complete blood counts during treatment and withhold TALVEY as recommended, based on severity.

Skin Toxicity: TALVEY can cause serious skin reactions, including rash, maculo-papular rash, erythema, and erythematous rash. In the clinical trial, skin reactions occurred in 62% of patients, with grade 3 skin reactions in 0.3%. The median time to onset was 25 (range: 1 to 630) days. The median time to improvement to grade 1 or less was 33 days.

Monitor for skin toxicity, including rash progression. Consider early intervention and treatment to manage skin toxicity. Withhold TALVEY as recommended based on severity.

Hepatotoxicity: TALVEY can cause hepatotoxicity. Elevated ALT occurred in 33% of patients, with grade 3 or 4 ALT elevation occurring in 2.7%; elevated AST occurred in 31% of patients, with grade 3 or 4 AST elevation occurring in 3.3%. Grade 3 or 4 elevations of total bilirubin occurred in 0.3% of patients. Liver enzyme elevation can occur with or without concurrent CRS.

Monitor liver enzymes and bilirubin at baseline and during treatment as clinically indicated. Withhold TALVEY or consider permanent discontinuation of TALVEY, based on severity [see Dosage and Administration (2.5)].

Embryo-Fetal Toxicity: Based on its mechanism of action, TALVEY may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with TALVEY and for 3 months after the last dose.

Adverse Reactions: The most common adverse reactions (≥20%) are pyrexia, CRS, dysgeusia, nail disorder, musculoskeletal pain, skin disorder, rash, fatigue, weight decreased, dry mouth, xerosis, dysphagia, upper respiratory tract infection, diarrhea, hypotension, and headache.

The most common Grade 3 or 4 laboratory abnormalities (≥30%) are lymphocyte count decreased, neutrophil count decreased, white blood cell decreased, and hemoglobin decreased.

Please read full Prescribing Information, including Boxed Warning, for TALVEY.

On December 11, 2023 During the ESMO (Free ESMO Whitepaper) Immuno-Oncology Congress 2023 held in Geneva, Switzerland, from December 6th to 8th, Qilu Pharmaceutical reported the latest results of the Phase I clinical trial for QLS31905 in patients with advanced solid tumors through a poster presentation (Poster No. 132P) (Press release, Qilu Pharmaceutical, DEC 11, 2023, View Source [SID1234638449]). The leading investigator of the study is Professor Lin Shen from the Peking University Cancer Hospital.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

QLS31905, developed by Qilu Pharmaceutical, is a bispecific T cell engager (BiTE) that targets Claudin18.2. The primary objective of this trial was to evaluate the safety, tolerability, and preliminary antitumor activity of QLS31905 in patients with advanced solid tumors.

Study Background and Design

Claudin18.2 is a highly specific cell surface molecule that is often abnormally expressed in primary gastric cancer as well as in other solid tumors such as pancreatic and esophageal cancers1,2. QLS31905 was designed to bind to Claudin18.2 on the surface of tumor cells and CD3 on the surface of T cells, leading to the sustained killing and lysis of tumor cells through the recruitment and activation of T cells near the tumor. This study enrolled patients with advanced solid tumors who had either failed standard treatments or for whom no standard treatment options were applicable or available. The trial consisted of two phases: dose escalation and dose expansion. In the dose-escalation phase, the accelerated titration and i3+3 designs were used. The dose levels of QLS31905 were incrementally increased, starting from 0.5 μg/kg once-weekly (QW), and escalated through 1.5 μg/kg QW, 5 μg/kg QW, 15 μg/kg QW, 45 μg/kg QW, 100 μg/kg QW, 200 μg/kg QW, 350 μg/kg QW, and up to 500 μg/kg biweekly (Q2W). The primary endpoints of this stage were the dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD), while secondary endpoints included safety, pharmacokinetics (PK), pharmacodynamics (PD) and immunogenicity. The dose-expansion phase focused on the objective response rate (ORR) as its primary endpoint. Secondary endpoints in this stage were the disease control rate (DCR), progression-free survival (PFS) and overall survival (OS).

Study Results

As of July 17, 2023, a total of 52 patients had been enrolled in the clinical trial, including 31 patients with gastric cancer and 12 with pancreatic cancer. During the dose-escalation phase, 22 participants received QLS31905 at 0.5 μg/kg QW to 350 μg/kg QW. The administration of the 500 μg/kg Q2W dose level is currently ongoing. In the dose-expansion phase, 30 patients had been enrolled and received QLS31905 at dose levels of 200 μg/kg QW and 350 μg/kg Q2W.

In terms of safety, no DLTs occurred, and the MTD had not been determined yet. Among all the participants, 21 (40.4%) experienced grade 3 or higher treatment-related adverse events (TRAEs), 10 (19.2%) experienced serious TRAEs, and two (3.8%) experienced TRAEs leading to the discontinuation of the treatment. The most common TRAEs included fever, which was observed in 30 patients (57.7%), nausea in 26 (50.0%), and a decrease in white blood cell counts in 18 (34.6%). Notably, grade 3 or higher cytokine release syndrome was reported in two patients in the 350 μg/kg QW cohort.

Regarding efficacy, out of the 27 participants who were evaluable for efficacy, the ORR was 11.1%, and the DCR reached 63.0%. Three patients achieved partial response (PR) and exhibited moderate to high levels of Claudin18.2 expression, including two patients with pancreatic cancer and one with gallbladder cancer. Furthermore, among the 14 patients who experienced stable disease, 8 reported a reduction in the size of target lesions, and 7 showed moderate to high Claudin18.2 expression.

In summary, QLS31905 has demonstrated favorable safety, tolerability, and preliminary antitumor activity in patients with advanced solid tumors. The Phase II clinical trial are now in progress to further assess the efficacy and safety of QLS31905.

On December 11, 2023 Kite, a Gilead Company (Nasdaq: GILD), reported data from follow-up analyses of three studies of Yescarta (axicabtagene ciloleucel) that demonstrate the long-term survival potential for patients living with several sub-types of relapsed or refractory (R/R) non-Hodgkin lymphoma, which were presented at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition (Press release, Gilead Sciences, DEC 11, 2023, View Source [SID1234638447]). This included ZUMA-1 (Abstract #4864) showing that patients with refractory large B-cell lymphoma (LBCL) who maintained a complete response (CR) at 12- and 24-months following treatment with Yescarta had a 72-month estimated disease-specific survival (DSS) of 94.4% and 100%, respectively. Long-term data from the ZUMA-5 (Abstract #4868) and ZUMA-7 (Abstract #1761) studies were also presented.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"As we continue to follow up with patients living with difficult-to-treat types of lymphomas, we are witnessing a pattern of longer-term survival with a one-time treatment with Yescarta," said Frank Neumann, MD, PhD, Senior Vice President, Global Head of Clinical Development, Kite. "The results of these studies, coupled with our rapid and reliable manufacturing, add to our body of knowledge on the benefits and utility of Yescarta as a treatment with curative intent, changing the way these cancers are treated and providing hope to thousands of lymphoma patients."

Detailed Information on Yescarta Abstracts:

Abstract #4864
Curative Potential of Axicabtagene Ciloleucel (Axi-Cel): an Exploratory Long-Term Survival Assessment in Patients with Refractory Large B-Cell Lymphoma from ZUMA-1

ZUMA-1 is an ongoing, multicenter, single-arm, open-label Phase 1/2 trial evaluating the safety and efficacy of Yescarta CAR T-cell therapy in adult patients with refractory LBCL. In this post hoc analysis of ZUMA-1, with up to six years of follow-up, the five-year long-term lymphoma-related event-free survival (LREFS) was used as a measure to explore Yescarta’s curative potential. Yescarta had long-term LREFS in a substantial proportion of patients, with a five-year rate of 34% (57% among patients who achieved a CR). Additionally, this exploratory analysis found that, at six years, median overall survival (OS) remained consistent with prior analyses at 25.8 months (95% Confidence Interval [CI], 12.8-63.7) and patients who had a CR at 12 and 24 months had a 72-month DSS of 94.4% and 100%, respectively, which may be predictive of extended OS. Among patients who had a CR to therapy, the leading risks of death were reasons other than progression or adverse events after month 24 post-infusion.

Abstract #4868
Axicabtagene Ciloleucel (Axi-Cel) in Patients with Relapsed/Refractory Indolent Non-Hodgkin Lymphoma: 4-Year Follow-Up from the Phase 2 ZUMA-5 Trial

ZUMA-5 is an ongoing, single-arm, open-label, international, multicenter Phase 2 trial evaluating 122 adult patients with R/R indolent non-Hodgkin lymphoma (iNHL; follicular lymphoma [FL] and marginal zone lymphoma [MZL]). In this study, at a median follow-up of 52.5 months (range, 20.3-69.4; FL: 53.7, MZL: 43.8), the overall response rate (ORR) remained consistent with prior analyses (90% ORR, 75% CR rate) and the median duration of response (DOR) was 55.5 months (95% CI, 38.6-not estimable [NE]; FL: 55.5, MZL: not reached). At data cutoff, four years of follow-up, median progression free survival (PFS) was 57.3 months (95% CI, 34.9-NE; FL: 57.3, MZL: 46.9) and the 48-month OS rate was 72% (FL: 72%, MZL: 68%). No new neurologic events, hypogammaglobulinemia cases, Grade ≥3 cytopenias or Grade ≥3 infections occurred in the four-year analysis compared to the three-year analysis.

"Taken together with other studies, the results we saw in our four-year analysis from the ZUMA-5 trial and up to six years of follow-up from the ZUMA-1 trial support the durability and safety of axi-cel in patients with follicular lymphoma and large B-cell lymphoma who have progressed following previous lines of therapy," said Dr. Sattva S. Neelapu, The University of Texas MD Anderson Cancer Center. "We are encouraged by these data, particularly the continued durable response and long-term survival in these patient populations that speak to the potentially curative benefit of this therapy. As we continue to follow these patients, our hope is that these positive survival trends are sustained."

Abstract #1761
Improved Overall Survival With Axicabtagene Ciloleucel vs Standard of Care in Second-Line Large B-Cell Lymphoma Among the Elderly: A Subgroup Analysis of ZUMA-7

ZUMA-7 is a randomized, open-label, global, multicenter, Phase 3 trial evaluating the safety and efficacy of Yescarta versus standard of care (SOC; [chemoimmunotherapy followed by HDT-ASCT in patients who had a response]) for treatment of adult patients with refractory LBCL or relapse within 12 months of first-line therapy. In this analysis, investigators reported updated efficacy and safety results from the primary OS analysis among ZUMA-7 patients aged ≥65 years and ≥70 years. At a median follow-up of 46.6 months, OS was prolonged in the Yescarta vs. SOC arm in patients aged ≥65 years (HR, 0.691; 95% CI, 0.401-1.190) and for those ≥70 y (HR, 0.330; 95% CI, 0.135-0.809). PFS assessed by investigator confirmed benefit of Yescarta over SOC in patients aged ≥65 years (HR, 0.406; 95% CI, 0.230‑0.715) and in patients aged ≥70 years (HR, 0.206; 95% CI, 0.078‑0.547). No new treatment-related deaths occurred since the primary event-free survival (EFS) analysis for ZUMA-7.

Yescarta Age 65+

SOC Age 65+

Yescarta Age 70+

SOC Age 70+

Median OS (months)

43.5 (95% CI, 20.9-NE)

19.5 (95% CI, 12.3-NE)

24.7 (95% CI, 12.8-NE)

11.2 (95% CI, 6.1-NE)

Median PFS (months)

28.6 (95% CI, 5.1-NE)

5.0 (95% CI, 2.8-7.3)

11.4 (95% CI, 4.1-NE)

2.7 (95% CI, 1.7-5.0)

"Traditionally, older patients with relapsed/refractory large B-cell lymphoma have not been able to access some treatments due to presumed concerns regarding increased toxicity related to their age and comorbidities," said Professor Marie José Kersten, Amsterdam University Medical Centers. "However, what we’re seeing with this subgroup analysis from the landmark ZUMA-7 trial, is that the data clearly support the consideration of axi-cel also for older patients with relapsed/refractory large B-cell lymphoma. As more data become available, my hope is that patients can receive the therapies that offer them the greatest chance for response and prolonged survival, regardless of age."

The Yescarta U.S. Prescribing Information has a BOXED WARNING for the risks of CRS and neurologic toxicities, and Yescarta is approved with a Risk Evaluation and Mitigation Strategy (REMS) due to these risks; see below for Important Safety Information.

About Follicular Lymphoma

FL is a form of iNHL in which malignant tumors slowly grow but can become more aggressive over time.

FL is the most common form of indolent lymphoma and the second most common type of lymphoma globally. It accounts for approximately 22 percent of all lymphomas diagnosed worldwide.

Despite advances in management and substantial improvements in long-term survival, patients living with FL have varied outcomes. Currently, there are no standard of care treatments for relapsed and refractory FL after two or more lines of therapy.

About Large B-Cell Lymphoma

Globally, LBCL is the most common type of NHL. In the United States, more than 18,000 people are diagnosed with LBCL each year. About 30-40% of patients with LBCL will need second-line treatment, as their cancer will either relapse (return) or become refractory (not respond) to initial treatment.

About Yescarta

Please see full US Prescribing Information, including BOXED WARNING and Medication Guide.

YESCARTA is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of:

Adult patients with large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy.
Adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.
Limitations of Use: YESCARTA is not indicated for the treatment of patients with primary central nervous system lymphoma.
Adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy. This indication is approved under accelerated approval based on the response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial(s).
U.S. IMPORTANT SAFETY INFORMATION

BOXED WARNING: CYTOKINE RELEASE SYNDROME AND NEUROLOGIC TOXICITIES

Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving YESCARTA. Do not administer YESCARTA to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving YESCARTA, including concurrently with CRS or after CRS resolution. Monitor for neurologic toxicities after treatment with YESCARTA. Provide supportive care and/or corticosteroids as needed.
YESCARTA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the YESCARTA and TECARTUS REMS Program.
CYTOKINE RELEASE SYNDROME (CRS)

CRS, including fatal or life-threatening reactions, occurred. CRS occurred in 90% (379/422) of patients with non-Hodgkin lymphoma (NHL), including ≥ Grade 3 in 9%. CRS occurred in 93% (256/276) of patients with large B-cell lymphoma (LBCL), including ≥ Grade 3 in 9%. Among patients with LBCL who died after receiving YESCARTA, 4 had ongoing CRS events at the time of death. For patients with LBCL in ZUMA-1, the median time to onset of CRS was 2 days following infusion (range: 1-12 days) and the median duration was 7 days (range: 2-58 days). For patients with LBCL in ZUMA-7, the median time to onset of CRS was 3 days following infusion (range: 1-10 days) and the median duration was 7 days (range: 2-43 days). CRS occurred in 84% (123/146) of patients with indolent non-Hodgkin lymphoma (iNHL) in ZUMA-5, including ≥ Grade 3 in 8%. Among patients with iNHL who died after receiving YESCARTA, 1 patient had an ongoing CRS event at the time of death. The median time to onset of CRS was 4 days (range: 1-20 days) and the median duration was 6 days (range: 1-27 days) for patients with iNHL.

Key manifestations of CRS (≥ 10%) in all patients combined included fever (85%), hypotension (40%), tachycardia (32%), chills (22%), hypoxia (20%), headache (15%), and fatigue (12%). Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), renal insufficiency, cardiac failure, respiratory failure, cardiac arrest, capillary leak syndrome, multi-organ failure, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome.

The impact of tocilizumab and/or corticosteroids on the incidence and severity of CRS was assessed in 2 subsequent cohorts of LBCL patients in ZUMA-1. Among patients who received tocilizumab and/or corticosteroids for ongoing Grade 1 events, CRS occurred in 93% (38/41), including 2% (1/41) with Grade 3 CRS; no patients experienced a Grade 4 or 5 event. The median time to onset of CRS was 2 days (range: 1-8 days) and the median duration of CRS was 7 days (range: 2-16 days). Prophylactic treatment with corticosteroids was administered to a cohort of 39 patients for 3 days beginning on the day of infusion of YESCARTA. Thirty-one of the 39 patients (79%) developed CRS and were managed with tocilizumab and/or therapeutic doses of corticosteroids with no patients developing ≥ Grade 3 CRS. The median time to onset of CRS was 5 days (range: 1-15 days) and the median duration of CRS was 4 days (range: 1-10 days). Although there is no known mechanistic explanation, consider the risk and benefits of prophylactic corticosteroids in the context of pre-existing comorbidities for the individual patient and the potential for the risk of Grade 4 and prolonged neurologic toxicities.

Ensure that 2 doses of tocilizumab are available prior to YESCARTA infusion. Monitor patients for signs and symptoms of CRS at least daily for 7 days at the certified healthcare facility, and for 4 weeks thereafter. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated.

NEUROLOGIC TOXICITIES

Neurologic toxicities (including immune effector cell-associated neurotoxicity syndrome) that were fatal or life-threatening occurred. Neurologic toxicities occurred in 78% (330/422) of all patients with NHL receiving YESCARTA, including ≥ Grade 3 in 25%. Neurologic toxicities occurred in 87% (94/108) of patients with LBCL in ZUMA-1, including ≥ Grade 3 in 31% and in 74% (124/168) of patients in ZUMA-7 including ≥ Grade 3 in 25%. The median time to onset was 4 days (range: 1-43 days) and the median duration was 17 days for patients with LBCL in ZUMA-1. The median time to onset for neurologic toxicity was 5 days (range: 1- 133 days) and the median duration was 15 days in patients with LBCL in ZUMA-7. Neurologic toxicities occurred in 77% (112/146) of patients with iNHL, including ≥ Grade 3 in 21%. The median time to onset was 6 days (range: 1-79 days) and the median duration was 16 days. Ninety-eight percent of all neurologic toxicities in patients with LBCL and 99% of all neurologic toxicities in patients with iNHL occurred within the first 8 weeks of YESCARTA infusion. Neurologic toxicities occurred within the first 7 days of infusion for 87% of affected patients with LBCL and 74% of affected patients with iNHL.

The most common neurologic toxicities (≥ 10%) in all patients combined included encephalopathy (50%), headache (43%), tremor (29%), dizziness (21%), aphasia (17%), delirium (15%), and insomnia (10%). Prolonged encephalopathy lasting up to 173 days was noted. Serious events, including aphasia, leukoencephalopathy, dysarthria, lethargy, and seizures occurred. Fatal and serious cases of cerebral edema and encephalopathy, including late-onset encephalopathy, have occurred.

The impact of tocilizumab and/or corticosteroids on the incidence and severity of neurologic toxicities was assessed in 2 subsequent cohorts of LBCL patients in ZUMA-1. Among patients who received corticosteroids at the onset of Grade 1 toxicities, neurologic toxicities occurred in 78% (32/41), and 20% (8/41) had Grade 3 neurologic toxicities; no patients experienced a Grade 4 or 5 event. The median time to onset of neurologic toxicities was 6 days (range: 1-93 days) with a median duration of 8 days (range: 1-144 days). Prophylactic treatment with corticosteroids was administered to a cohort of 39 patients for 3 days beginning on the day of infusion of YESCARTA. Of those patients, 85% (33/39) developed neurologic toxicities, 8% (3/39) developed Grade 3, and 5% (2/39) developed Grade 4 neurologic toxicities. The median time to onset of neurologic toxicities was 6 days (range: 1-274 days) with a median duration of 12 days (range: 1-107 days). Prophylactic corticosteroids for management of CRS and neurologic toxicities may result in a higher grade of neurologic toxicities or prolongation of neurologic toxicities, delay the onset of and decrease the duration of CRS.

Monitor patients for signs and symptoms of neurologic toxicities at least daily for 7 days at the certified healthcare facility, and for 4 weeks thereafter, and treat promptly.

REMS

Because of the risk of CRS and neurologic toxicities, YESCARTA is available only through a restricted program called the YESCARTA and TECARTUS REMS Program which requires that: Healthcare facilities that dispense and administer YESCARTA must be enrolled and comply with the REMS requirements and must have on-site, immediate access to a minimum of 2 doses of tocilizumab for each patient for infusion within 2 hours after YESCARTA infusion, if needed for treatment of CRS. Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense, or administer YESCARTA are trained in the management of CRS and neurologic toxicities. Further information is available at www.YescartaTecartusREMS.com or 1-844-454-KITE (5483).

HYPERSENSITIVITY REACTIONS

Allergic reactions, including serious hypersensitivity reactions or anaphylaxis, may occur with the infusion of YESCARTA.

SERIOUS INFECTIONS

Severe or life-threatening infections occurred. Infections (all grades) occurred in 45% of patients with NHL; ≥ Grade 3 infections occurred in 17% of patients, including ≥ Grade 3 infections with an unspecified pathogen in 12%, bacterial infections in 5%, viral infections in 3%, and fungal infections in 1%. YESCARTA should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after infusion and treat appropriately. Administer prophylactic antimicrobials according to local guidelines.

Febrile neutropenia was observed in 36% of all patients with NHL and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids, and other supportive care as medically indicated.

In immunosuppressed patients, including those who have received YESCARTA, life-threatening and fatal opportunistic infections including disseminated fungal infections (e.g., candida sepsis and aspergillus infections) and viral reactivation (e.g., human herpes virus-6 [HHV-6] encephalitis and JC virus progressive multifocal leukoencephalopathy [PML]) have been reported. The possibility of HHV-6 encephalitis and PML should be considered in immunosuppressed patients with neurologic events and appropriate diagnostic evaluations should be performed.

Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against B cells, including YESCARTA. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.

PROLONGED CYTOPENIAS

Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and YESCARTA infusion. ≥ Grade 3 cytopenias not resolved by Day 30 following YESCARTA infusion occurred in 39% of all patients with NHL and included neutropenia (33%), thrombocytopenia (13%), and anemia (8%). Monitor blood counts after infusion.

HYPOGAMMAGLOBULINEMIA

B-cell aplasia and hypogammaglobulinemia can occur. Hypogammaglobulinemia was reported as an adverse reaction in 14% of all patients with NHL. Monitor immunoglobulin levels after treatment and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement. The safety of immunization with live viral vaccines during or following YESCARTA treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during YESCARTA treatment, and until immune recovery following treatment.

SECONDARY MALIGNANCIES

Secondary malignancies may develop. Monitor life-long for secondary malignancies. In the event that one occurs, contact Kite at 1-844-454-KITE (5483) to obtain instructions on patient samples to collect for testing.

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

Due to the potential for neurologic events, including altered mental status or seizures, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following YESCARTA infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.

ADVERSE REACTIONS

The most common non-laboratory adverse reactions (incidence ≥ 20%) in patients with LBCL in ZUMA-7 included fever, CRS, fatigue, hypotension, encephalopathy, tachycardia, diarrhea, headache, musculoskeletal pain, nausea, febrile neutropenia, chills, cough, infection with an unspecified pathogen, dizziness, tremor, decreased appetite, edema, hypoxia, abdominal pain, aphasia, constipation, and vomiting.

The most common adverse reactions (incidence ≥ 20%) in patients with LBCL in ZUMA-1 included CRS, fever, hypotension, encephalopathy, tachycardia, fatigue, headache, decreased appetite, chills, diarrhea, febrile neutropenia, infections with an unspecified, nausea, hypoxia, tremor, cough, vomiting, dizziness, constipation, and cardiac arrhythmias.

The most common non-laboratory adverse reactions (incidence ≥ 20%) in patients with iNHL in ZUMA-5 included fever, CRS, hypotension, encephalopathy, fatigue, headache, infections with an unspecified, tachycardia, febrile neutropenia, musculoskeletal pain, nausea, tremor, chills, diarrhea, constipation, decreased appetite, cough, vomiting, hypoxia, arrhythmia, and dizziness.

On December 11, 2023 Harpoon Therapeutics, Inc. (Nasdaq: HARP), a clinical-stage immunotherapy company developing novel T cell engagers, reported data from the Phase 1 study of HPN217 in patients with RRMM in an oral presentation at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in San Diego (Press release, Harpoon Therapeutics, DEC 11, 2023, View Source [SID1234638446]). Harpoon also announced the selection of 12 mg as the HPN217 RP2D.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

During the trial, 97 patients with RRMM who had received at least three prior therapies were enrolled across 15 dose escalation cohorts and three expansion regimens. As of the data cut-off of October 17, 2023, the data demonstrated:

Clinical activity across a wide dose range (2.15 mg to 24 mg). The maximum tolerated dose (MTD) was not reached at the target dose using a step up approach.
Optimal activity and safety profile was seen at 12 mg, which was declared the RP2D.
The Overall Response Rate (ORR) across 12 mg cohorts was 63% (12/19, 95% CI: 38, 84). In addition, the depth of response was most significant at 12 mg, with 53% (10/19) of patients having a Very Good Partial Response (VGPR) or better.
The median time to first response in the 12 mg and 24 mg cohort was 1.2 months, and the median duration of response for all responders was 20.5 months as of the data cutoff date. Out of all the responders, 58% (22/38) remain on treatment.
In the 12 mg and 24 mg cohorts, nine patients were previously exposed to BCMA-targeting agents, and six of those patients responded to the HPN217 treatment.
The incidence of cytokine release syndrome (CRS) was lowest (16%) in the 12 mg cohorts, all Grade 1-2. No immune effector cell associated neurotoxicity syndrome (ICANS) events were observed at the 12 mg dose.
"The data presented at ASH (Free ASH Whitepaper) today demonstrates that HPN217 has the potential to provide a meaningful benefit for patients with relapsed/refractory multiple myeloma, even in patients with prior anti-BCMA therapy," said Sumit Madan, M.D., Hematologist and Oncologist at Banner MD Anderson Cancer Center and Associate Professor (Adj) of Myeloma and Lymphoma at UT MD Anderson Cancer Center. "The low rate of CRS seen in this study is noteworthy and can help enable future studies of HPN217 in combination and in earlier lines of therapy."

"The HPN217 Phase 1 data set represents important progress for the program and validates the potential of HPN217 to deliver a wider therapeutic index. We observed a compelling 63% response rate in patients treated with the 12 mg target dose, with only a 16% rate of CRS," said Luke Walker, M.D., Chief Medical Officer for Harpoon Therapeutics. "These data and our interactions with the FDA have enabled us to declare a RP2D that can be used to support further clinical development."

For more details about the ASH (Free ASH Whitepaper) Annual Meeting, please visit: View Source

For additional information about the trial, please visit www.clinicaltrials.gov using the identifier NCT04184050.

The presentation will also be available on Harpoon’s website under Publications following the session.

About HPN217
HPN217 targets B-cell maturation antigen (BCMA) and is based on Harpoon’s proprietary Tri-specific T cell Activating Construct (TriTAC) platform designed to recruit a patient’s own immune cells to kill tumor cells. BCMA, a clinically validated target, is a tumor necrosis factor receptor super family member and is a receptor protein expressed on nearly all multiple myeloma cells.

On December 11, 2023 Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) reported two oral presentations at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition from the global pivotal trials of CASGEVY (exagamglogene autotemcel [exa-cel]) (Press release, Vertex Pharmaceuticals, DEC 11, 2023, View Source [SID1234638445]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Data from 96 patients (44 sickle cell disease [SCD], 52 transfusion-dependent beta thalassemia [TDT]) treated with CASGEVY in pivotal studies, with the longest follow-up of more than four years, continue to reinforce the consistent and durable response to treatment. In addition, new data illustrating improvements in patient-reported outcomes after treatment with CASGEVY were featured in poster presentations at ASH (Free ASH Whitepaper).

"We are excited to share this comprehensive data set with the broader community today, just days after FDA approval of CASGEVY for the treatment of severe sickle cell disease," said Carmen Bozic, M.D., Executive Vice President, Global Medicines Development and Medical Affairs, and Chief Medical Officer at Vertex. "These data demonstrate the consistent and durable efficacy of CASGEVY in eliminating severe vaso-occlusive crises in patients with SCD and conferring transfusion independence in patients with TDT."

CASGEVY is approved by the U.S. Food and Drug Administration (FDA) for the treatment of sickle cell disease in patients 12 years of age and older with recurrent vaso-occlusive crises (VOCs). The use of CASGEVY for the treatment of TDT in the U.S. remains investigational. Vertex has submitted a BLA to the U.S. FDA for the potential use of CASGEVY for patients 12 years and older with TDT and has been assigned a Prescription Drug User Fee Act (PDUFA) target action date of March 30, 2024.

In addition to the two oral presentations, there are additional poster presentations by Vertex at ASH (Free ASH Whitepaper).

Oral presentation, Abstract #1052, entitled "Exagamglogene Autotemcel for Severe Sickle Cell Disease"
Oral presentation, Abstract #1053, entitled "Exagamglogene Autotemcel for Transfusion-Dependent Βeta-Thalassemia"
Poster Presentation, Abstract #4997, entitled "Improvements In Health-Related Quality of Life After Exagamglogene Autotemcel in Patients with Transfusion-Dependent Beta Thalassemia"
Poster Presentation, Abstract #4999, entitled "Improvements In Health-Related Quality of Life After Exagamglogene Autotemcel in Patients With Severe Sickle Cell Disease"
Poster Presentation, Abstract #3674, entitled "VOC-free Status Among Patients with Sickle Cell Disease Following Allogeneic Hematopoietic Stem Cell Transplant: A Cohort Study of Medicaid Enrollees"
Poster Presentation, Abstract #3678, entitled "The Impact of Recent Vaso-Occlusive Crisis on Health-Related Quality of Life in Adults with Sickle Cell Disease"
Poster Presentation, Abstract #3900, entitled "Estimating Sickle Cell Disease Prevalence by State: A Model Using US-born and Foreign-born State-specific Population Data"
About Sickle Cell Disease (SCD)

SCD is a debilitating, progressive, life-shortening genetic disease. SCD patients report health-related quality of life scores well below the general population, and the lifetime health care costs in the U.S. of managing SCD for patients with recurrent VOCs is estimated between $4 and $6 million. SCD affects the red blood cells, which are essential for carrying oxygen to all organs and tissues of the body. SCD causes severe pain, organ damage and shortened life span due to misshapen or "sickled" red blood cells. The clinical hallmark of SCD is VOCs, which are caused by blockages of blood vessels by sickled red blood cells and result in severe and debilitating pain that can happen anywhere in the body at any time. SCD requires lifelong treatment and significant use of health care resources, and ultimately results in reduced life expectancy, decreased quality of life and reduced lifetime earnings and productivity. In the U.S., the median age of death for patients living with SCD is 45 years. Stem cell transplant from a matched donor is a curative option but is only available to a small fraction of patients living with SCD because of the lack of available donors.

About Transfusion-Dependent Beta Thalassemia (TDT)

TDT is a serious, life-threatening genetic disease. TDT patients report health-related quality of life scores below the general population, and the lifetime health care costs in the U.S. of managing TDT are estimated between $5 and $5.7 million. TDT requires frequent blood transfusions and iron chelation therapy throughout a person’s life. Due to anemia, patients living with TDT may experience fatigue and shortness of breath, and infants may develop failure to thrive, jaundice and feeding problems. Complications of TDT can also include an enlarged spleen, liver and/or heart, misshapen bones and delayed puberty. TDT requires lifelong treatment and significant use of health care resources, and ultimately results in reduced life expectancy, decreased quality of life and reduced lifetime earnings and productivity. In the U.S., the median age of death for patients living with TDT is 37 years. Stem cell transplant from a matched donor is a curative option but is only available to a small fraction of patients living with TDT because of the lack of available donors.

About CASGEVY (exagamglogene autotemcel [exa-cel])

CASGEVY is a genome-edited cellular therapy consisting of autologous CD34+ hematopoietic stem cells (HSCs) edited by CRISPR/Cas9 technology at the erythroid-specific enhancer region of the BCL11A gene. CASGEVY is intended for one time administration via a hematopoietic stem cell transplant procedure where the patient’s own CD34+ cells are modified to reduce BCL11A expression in erythroid lineage cells, leading to increased fetal hemoglobin (HbF) production. HbF is the form of the oxygen-carrying hemoglobin that is naturally present during fetal development, which then switches to the adult form of hemoglobin after birth. CASGEVY has been shown to reduce or eliminate vaso-occlusive crises for patients with SCD.

CASGEVY was granted a conditional marketing authorization in Great Britain by the U.K. Medicines and Healthcare products Regulatory Agency and by the National Health Regulatory Authority in Bahrain for patients 12 years of age and older with SCD characterized by recurrent vaso-occlusive crises or TDT, for whom hematopoietic stem cell transplantation is appropriate and a human leukocyte antigen matched related hematopoietic stem cell donor is not available. CASGEVY is currently under review by the European Medicines Agency and the Saudi Food and Drug Agency for both SCD and TDT.

U.S. INDICATIONS AND IMPORTANT SAFETY INFORMATION FOR CASGEVY (exagamglogene autotemcel)

WHAT IS CASGEVY?

CASGEVY is a one-time therapy used to treat people aged 12 years and older with sickle cell disease (SCD) who have frequent vaso-occlusive crises or VOCs.

CASGEVY is made specifically for each patient, using the patient’s own edited blood stem cells, and increases the production of a special type of hemoglobin called hemoglobin F (fetal hemoglobin or HbF). Having more HbF increases overall hemoglobin levels and has been shown to improve the production and function of red blood cells. This can eliminate VOCs in people with SCD.

IMPORTANT SAFETY INFORMATION

What is the most important information I should know about CASGEVY?

After treatment with CASGEVY, you will have fewer blood cells for a while until CASGEVY takes hold (engrafts) into your bone marrow. This includes low levels of platelets (cells that usually help the blood to clot) and white blood cells (cells that usually fight infections). Your doctor will monitor this and give you treatment as required. The doctor will tell you when blood cell levels return to safe levels.

Tell your healthcare provider right away if you experience any of the following, which could be signs of low levels of platelet cells:
severe headache
abnormal bruising
prolonged bleeding
bleeding without injury such as nosebleeds; bleeding from gums; blood in your urine, stool, or vomit; or coughing up blood
Tell your healthcare provider right away if you experience any of the following, which could be signs of low levels of white blood cells:
fever
chills
infections
You may experience side effects associated with other medicines administered as part of the treatment regimen with CASGEVY. Talk to your physician regarding those possible side effects. Your healthcare provider may give you other medicines to treat your side effects.

How will I receive CASGEVY?

Your healthcare provider will give you other medicines, including a conditioning medicine, as part of your treatment with CASGEVY. It’s important to talk to your healthcare provider about the risks and benefits of all medicines involved in your treatment.

After receiving the conditioning medicine, it may not be possible for you to become pregnant or father a child. You should discuss options for fertility preservation with your healthcare provider before treatment.

STEP 1: Before CASGEVY treatment, a doctor will give you a mobilization medicine. This medicine moves blood stem cells from your bone marrow into the blood stream. The blood stem cells are then collected in a machine that separates the different blood cells (this is called apheresis). This entire process may happen more than once. Each time, it can take up to one week.

During this step, rescue cells are also collected and stored at the hospital. These are your existing blood stem cells and are kept untreated just in case there is a problem in the treatment process. If CASGEVY cannot be given after the conditioning medicine, or if the modified blood stem cells do not take hold (engraft) in the body, these rescue cells will be given back to you. If you are given rescue cells, you will not have any treatment benefit from CASGEVY.

STEP 2: After they are collected, your blood stem cells will be sent to the manufacturing site where they are used to make CASGEVY. It may take up to 6 months from the time your cells are collected to manufacture and test CASGEVY before it is sent back to your healthcare provider.

STEP 3: Shortly before your stem cell transplant, your healthcare provider will give you a conditioning medicine for a few days in hospital. This will prepare you for treatment by clearing cells from the bone marrow, so they can be replaced with the modified cells in CASGEVY. After you are given this medicine, your blood cell levels will fall to very low levels. You will stay in the hospital for this step and remain in the hospital until after the infusion with CASGEVY.

STEP 4: One or more vials of CASGEVY will be given into a vein (intravenous infusion) over a short period of time.

After the CASGEVY infusion, you will stay in hospital so that your healthcare provider can closely monitor your recovery. This can take 4-6 weeks, but times can vary. Your healthcare provider will decide when you can go home.

What should I avoid after receiving CASGEVY?

Do not donate blood, organs, tissues, or cells at any time in the future
What are the possible or reasonably likely side effects of CASGEVY?

The most common side effects of CASGEVY include:

Low levels of platelet cells, which may reduce the ability of blood to clot and may cause bleeding
Low levels of white blood cells, which may make you more susceptible to infection
Your healthcare provider will test your blood to check for low levels of blood cells (including platelets and white blood cells). Tell your healthcare provider right away if you get any of the following symptoms:

fever
chills
infections
severe headache
abnormal bruising
prolonged bleeding
bleeding without injury such as nosebleeds; bleeding from gums; blood in your urine, stool, or vomit; or coughing up blood
These are not all the possible side effects of CASGEVY. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about the safe and effective use of CASGEVY

Talk to your healthcare provider about any health concerns.

Please see full Prescribing Information including Patient Information for CASGEVY.