Enfortumab vedotin (Padcev) produced promising antitumor activity when used as neoadjuvant treatment in patients with muscle invasive bladder cancer (MIBC) who were not eligible for cisplatin, according to preliminary findings from cohort H of the phase 1b/2 EV-103 trial (NCT03288545) presented during the 

Investigators reported a pathological complete response (pCR) rate of 36.4% (95% CI, 17.2%-59.3%) among those treated with enfortumab vedotin (n = 22), as well as a pathological downstaging (pDS) rate of 50.0% (95% CI, 28.2%-71.8%).

“This first disclosure of data supports the ongoing phase 2 and 3 programs evaluating enfortumab vedotin alone or in combination with pembrolizumab in MIBC,” Daniel Petrylak, MD, professor of medical oncology and urology at the Yale Cancer Center, said in his presentation of the data.

Eligibility required patients to be ineligible for cisplatin, have clinical T2-T4N0M0 disease, and no upper tract or urethral tumors. Additionally, a urothelial carcinoma histology of greater than 50% was required. Patients also needed to have an ECOG performance status of 0 to 2, be medically fit for radical cystectomy plus pelvic lymph node dissection and have undergone transurethral resection of bladder tumor within 90 days of the first day of cycle 1.

Patients received 1.25 mg/kg of neoadjuvant enfortumab vedotin monotherapy on days 1 and 8 per 21-day cycle for 3 cycles. Within 4 weeks of treatment, patients underwent radical cystectomy plus pelvic lymph node dissection followed by imaging every 12 weeks for the first 2 years and then every 24 weeks after.

The primary end point was pCR by central pathology review. Secondary end points included pDS by central review, event-free survival, disease-free survival, overall survival, safety, patient-reported outcomes, and biomarkers.

The median age of the study population was 74.5 years. All patients were White, and most patients were male (90.9%) and a current or former smoker (95.5%). Most patients had an ECOG performance status of 0 (59.1%) followed by 1 (36.4%) and 2 (4.5%).

The most common reason for cisplatin-ineligibility was creatine clearance between less than 60 to 30 or more mL per minute (50.0%), followed by grade 2 or greater hearing loss (40.9%). A total of 86% of patients completed all 3 cycles of neoadjuvant therapy.

Any grade enfortumab vedotin–related treatment emergent adverse effects (TEAEs) were seen in all patients, with common TEAEs including fatigue (45.5%), alopecia (36.4%), dysgeusia (36.4%), diarrhea (27.3%), nausea (27.3%), peripheral sensory neuropathy (27.3%), dry eye (22.7%), and maculopapular rash (22.7%). Four patients experienced grade 3 or higher TEAEs, and no grade 4 TEAEs or deaths were reported. Grade 3 TEAEs related to treatment with enfortumab vedotin included asthenia, dehydration, erythema multiforme, and hyperglycemia.

Three enfortumab vedotin–related TEAEs leading to dose interruptions, 2 TEAEs leading to dose reductions, and 3 TEAEs leading to discontinuations were observed in the safety analysis. Most AEs of special interest were grade 1 and 2. Any grade AEs of interest included peripheral neuropathy (36.4%), skin reaction (63.6%), hyperglycemia (22.7%), ocular disorder (40.9%), and infusion-related reactions (9.1%). Grade 3 or greater AEs of special interest were skin reactions (9.1%) and hyperglycemia (13.6%).

“The observed safety profile of neoadjuvant enfortumab vedotin monotherapy in patients with cisplatin-ineligible MIBC is consistent with the known AE profile of enfortumab vedotin in other settings,” Petrylak concluded.

Petrylak DP, Flaig TW, Mar N, et al. Study EV-103 Cohort H: Antitumor activity of neoadjuvant treatment with enfortumab vedotin monotherapy in patients (pts) with muscle invasive bladder cancer (MIBC) who are cisplatin-ineligible. 

. 2022;40(suppl 6):435. doi: 10.1200/JCO.2022.40.6_suppl.435

Articles

Enfortumab vedotin produced promising antitumor activity when used as neoadjuvant treatment in patients with muscle invasive bladder cancer who were not eligible for cisplatin.

Neoadjuvant Enfortumab Vedotin Demonstrates Encouraging Activity in Cisplatin-Ineligible Muscle-Invasive Bladder Cancer

The subcutaneous combination of the BCMA-targeting bispecific antibody teclistamab (JNJ-64007957) and daratumumab (Darzalex) produced promising preliminary efficacy and favorable tolerability in heavily pretreated patients with relapsed or refractory multiple myeloma, according to results from the phase 1b TRIMM-2 trial (NCT04108195).

The results, which were presented during the 

, showed that at a median follow-up of 5.1 months (range, 0.3-12.9), evaluable patients in the first cohort who received teclistamab at 3 mg/kg once every 2 weeks (n = 10) experienced an ORR of 70.0%, with 60.0% of patients achieving a very good partial response (VGPR) and 10.0% experiencing a partial response (PR). Moreover, 30% of patients had stable disease.

Evaluable patients in the second cohort who were administered teclistamab at 1.5 mg/kg once weekly (n = 19) achieved an ORR of 84.0%. Of those who responded, 31.6% achieved a complete response (CR), 36.8% experienced a VGPR, and 15.8% had a PR. Additionally, 5.3% of patients had stable disease, and 10.5% experienced disease progression. Evaluable patients in the third cohort who received teclistamab at 3 mg/kg weekly (n = 4) experienced an ORR of 100%; 75% achieved a CR and 25% had a VGPR.

“The preclinical data showed that daratumumab, an anti-CD38 monoclonal antibody, may lead to synergistic clinical efficacy when combined with teclistamab, a bispecific antibody targeting BCMA,” lead study author Paula Rodriguez-Otero, MD, Department of Hematology, Clínica Universidad de Navarra, Pamplona, Spain, said in an interview with 

®. “[We have data showing that] daratumumab monotherapy [lead] to T-cell expansion and enhanced T-cell cytotoxic potential, [and] preclinical studies showed that the addition of daratumumab may enhance the teclistamab-mediated lysis of myeloma cells.”

Prior data from the phase 1 MajesTEC-1 trial (NCT04557098) showed that teclistamab monotherapy, when given at the recommended phase 2 dose (RP2D), elicited an ORR of 65% and a VGPR or better rate of 56% in heavily pretreated patients with relapsed or refractory multiple myeloma at a median follow-up of 6.1 months (range, 1.2-15.2).

TRIMM-2 enrolled patients who were at least 18 years of age and who had a diagnosis of multiple myeloma based on the International Myeloma Working Group criteria. Eligible patients were required to have received at least 3 prior lines of therapy, including a proteasome inhibitor (PI) and immunomodulatory drug (IMiD), or to have been double refractory to a PI and IMiD. Notably, patients who received anti-CD38 therapy within 90 days were excluded from the study. Patients who were outside of the 90-day window or refractory to anti-CD38 therapy were eligible.

Across the 3 cohorts, a total of 37 patients received subcutaneous teclistamab at a weekly dose of 1.5 mg/kg weekly, a weekly dose of 3 mg/kg weekly, or at 3 mg/kg given every other week. Nine patients had a schedule change from teclistamab 1.5 mg/kg weekly to 3 mg/kg every other week for cycles 4 through 9. Notably, there was no steroid requirement for teclistamab after the first cycle. All patients were also administered subcutaneous daratumumab at a weekly dose of 1800 mg for the first 2 cycles, every other week for cycles 3 through 6, and monthly beyond cycle 7.

Responses were assessed per International Myeloma Working Group 2016 criteria. Additionally, adverse effects (AEs) were evaluated per Common Terminology Criteria for Adverse Events v5.0, except for cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS), which were assessed using American Society for Transplantation and Cellular Therapy criteria.

The primary end points of the trial were to identify the RP2D for each treatment combination and characterize the safety of each regimen at the selected doses. Additional end points of interest included antitumor activity, pharmacokinetics, pharmacodynamics.

The median age of enrolled patients across all 3 cohorts was 67 years (range, 51-79), and 54.1% were female. Moreover, 24.3% of patients had at least 1 extramedullary plasmacytoma and 25.9% had high-risk cytogenetics. The median time since diagnosis was 6.7 years (range, 0.7-14.2), and the median prior number of therapies received was 5 (range, 2-16). Additionally, 73% of patients underwent prior stem cell transplantation. Additionally, 75.7% had previously been exposed to anti-CD38 therapies, 75.7% were triple-class exposed, and 59.5% were penta-drug exposed.

Additional data showed the median time to first confirmed response across all groups was 1.0 month (range, 1.0-2.8). The ORR was also found to have improved with the addition of daratumumab vs the RP2D of 1.5 mg/kg of teclistamab monotherapy. At a median follow-up of 6.5 months (range, 1.2-12.9), 92.6% of responders were still on treatment.

Peripheral T-cell activation was noted with teclistamab/daratumumab, which was shown by the upregulation of CD38-/CD8-positive T cells. The proportion of CD38-/CD8-positive T cells declined after initial daratumumab dosing on day 1 of cycle 1, and teclistamab administration resulted in the induction of CD38-positive T cells after cycle 1 day 2, despite concurrent daratumumab treatment. After teclistamab dosing in the presence of daratumumab, the induction of pro-inflammatory cytokines was observed. The pharmacokinetic profile of teclistamab in the presence of daratumumab was consistent with the profile that was observed in the MajesTEC-1 trial.

No new AEs were observed vs when either agent was used as a monotherapy, and no toxicities resulted in treatment discontinuations. All CRS events were grade 1 or 2 in severity. One patient had grade 2 ICANS, which resolved in 5 days. Infections were experienced by 59.5% of patients, with 29.7% experiencing grade 3 or higher events.

Hematologic AEs neutropenia, anemia, and thrombocytopenia of any grade were reported in 51.4%, 45.9%, and 32.4% of patients, respectively. Grade 3 or 4 neutropenia, anemia, and thrombocytopenia occurred in 45.9%, 29.7%, and 32.4% of patients, respectively. The most common nonhematologic AEs of any grade were CRS (64.9%), diarrhea (35.1%), nausea (29.7%), asthenia (29.7%), fatigue (27.0%), pyrexia (24.3%), and headache (24.3%).

The data reported from all 3 cohorts of the trial support further exploration of the combination, according to the study authors.

To this end, the phase 3 MajesTEC-3 study (NCT05083169) will evaluate teclistamab plus daratumumab vs daratumumab, pomalidomide (Pomalyst), and dexamethasone, or daratumumab, bortezomib (Velcade), and dexamethasone.

“The combination of teclistamab and daratumumab [shows] preliminary efficacy [with] a promising ORR that could be even higher [than] the efficacy [achieved with] teclistamab as a single agent,” Rodriguez-Otero concluded. “It is the basis of an ongoing phase 3 study [called] MajesTEC-3, [which] is further evaluating the combination of teclistamab plus daratumumab in relapsed/refractory multiple myeloma.”

Rodriguez-Otero P, Dholaria B, Askari E, et al. Subcutaneous teclistamab in combination with daratumumab for the treatment of patients with relapsed/refractory multiple myeloma: results from a phase 1b multicohort study. 

. 2021;138(suppl 1):1647. doi:10.1182/blood-2021-148723

Moreau P, Usmani SZ, Garfall AL, et al. Updated results from majestec-1: phase 1/2 study of teclistamab, a B-cell maturation antigen x CD3 bispecific antibody, in relapsed/refractory multiple myeloma. 

. 2021;138(suppl 1):896. doi:10.1182/blood-2021-147915

The subcutaneous combination of the BCMA-targeting bispecific antibody teclistamab and daratumumab produced promising preliminary efficacy and favorable tolerability in heavily pretreated patients with relapsed or refractory multiple myeloma, according to results from the phase 1b TRIMM-2 trial.

Teclistamab/Daratumumab Combo Elicits Encouraging Responses in Relapsed/Refractory Myeloma

Significant progress has been made toward the initiation of the phase 3 FLAMINGO-01 trial, which will evaluate the combination of the immunotherapy GP2 with granulocyte macrophage colony stimulating factor (GM-CSF; GLSI-100) in the adjuvant treatment of HER2/neu- and HLA-A*02–positive patients following surgery and trastuzumab (Herceptin)-based therapy.

GP2 is a biologic 9 amino acid peptide of the HER2/neu protein; the agent will be delivered in combination with the FDA-approved GM-CSF, which will serve to stimulate an immune response and target HER2/neu-expressing cancers.

Greenwich LifeSciences, Inc., the developer of GP2, has announced that a contract research organization has been contracted for the start-up of the trial, along with project and data management and clinical data monitoring. Moreover, the third clinical lot of the product using a commercial line has been manufactured, and commercial lots of the GP2 active ingredient has been contracted so that the biologics license application can be filed.

Additionally, the central laboratory has been contracted to screen for HLA type, and drug and biological sample storage sites, along with other trial infrastructure, has also been put into place. The study has also been granted approval from the Central Institutional Review Board.

Previously, results from a prespecified subgroup analysis of a prospective, randomized, single-blinded, placebo-controlled, multicenter phase 2b trial showed that after a median 5 years of follow-up, no recurrences were observed in the HER2/neu-positive adjuvant setting if the HLA-A*02–positive patient was given the 6 primary intradermal GP2 injections over the first 6 months (

 = .0338). GP2 was also found to induce a strong immune response per local skin tests and immunological assays.

With the prospective, randomized, double-blinded, multicenter FLAMINGO-01 trial, investigators seek to reproduce the phase 2b trial and further explore the use of GLSI-100 in HER2/neu- and HLA-A*02–positive patients, following surgery and the first year of treatment with any trastuzumab-based therapy or an approved biosimilar.

Additional major screening criteria include having residual disease following neoadjuvant therapy and surgery, and pathologic complete response (pCR) if the patient has stage IIII disease at the time of presentation. Patients with stage IV disease will be excluded.

First, patients will undergo a screening period and within 3 months prior to the end of their trastuzumab-based treatment, they will be screened for HLA type. After treatment with the trastuzumab-based therapy has come to completion, HLA-A*02–positive patients will be randomized to GLSI-100 or saline placebo.

Participants will receive 6 intradermal injections of GLSI-100 or saline placebo for the primary immunization series over the first 6 months. They will subsequently receive 5 boosters over the next 2.5 years, equating to total of 11 injections over 3 years of treatment. There will be 1 additional year of follow-up for a total of 4 years after the first year of treatment with a trastuzumab-based therapy.

Key stratification factors will include residual disease/pCR, prior pertuzumab (Perjeta), and geographic region.

The key objectives of the research are to identify whether GP2 increases invasive disease-free survival (iDFS), to evaluate the safety profile of the immunotherapy, and to monitor immunologic responses to treatment and examine relationship to efficacy and safety.

Investigators anticipate enrolling approximately 498 patients to FLAMINGO-01. To detect a hazard ratio of 0.3 in iDFS, a total of 28 events will be required. An interim analysis for superiority and futility is planned to occur when at least 14 events have occurred. This sample size provides 80% power if the annual rate of events in placebo-treated subjects is 2.4% or greater.

Clinical trial sites continue to proceed through the study start-up process and the clinical-stage biopharmaceutical company shared that they will continue to solicit additional sites and networks in the United States and on an international level for study participation.

Greenwich LifeSciences provides update on upcoming phase III clinical trial, FLAMINGO-01. News release. Greenwich LifeSciences, Inc.; February 1, 2022. Accessed February 2, 2022. 

Patel SS, McWilliams DB, Fischette CT, et al. A prospective, randomized, multicenter, double-blinded, placebo-controlled phase III trial of the HER2/neu GP2 + GM-CSF (GLSI-100) versus saline placebo as adjuvant therapy after trastumab-based therapy in HER2-positive women with operable breast cancer (FLAMINGO-01). Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, Texas. Accessed February 2, 2022. 

Significant progress has been made toward the initiation of the phase 3 FLAMINGO-01 trial, which will evaluate the combination of the immunotherapy GP2 with granulocyte macrophage colony stimulating factor in the adjuvant treatment of HER2/neu- and HLA-A*02–positive patients following surgery and trastuzumab-based therapy.

Pipeline Report: February 2022

Articles

Neoadjuvant Enfortumab Vedotin Demonstrates Encouraging Activity in Cisplatin-Ineligible Muscle-Invasive Bladder Cancer

Teclistamab/Daratumumab Combo Elicits Encouraging Responses in Relapsed/Refractory Myeloma