efbalropoendekin alfa (RG6323) / Xencor, Roche - LARVOL DELTA

An Open-Label Dose-Escalation Study to Evaluate XmAb24306 as a Single Agent and in Combination With Atezolizumab in Participants With Locally Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1 | N=195 | Active, not recruiting | Sponsor: Genentech, Inc. | Trial completion date: Dec 2025 ➔ Dec 2026 | Trial primary completion date: Dec 2025 ➔ Dec 2026

Trial completion date • Trial primary completion date • Solid Tumor

A quantitative systems pharmacology model to inform clinical translation of dynamic PKPD relationships of engineered IL-15. (PubMed, Eur J Pharm Sci) - "In this work, we develop a quantitative systems pharmacology (QSP) model to capture the dynamics of lymphocyte expansion in response to three engineered IL-15/IL-15Rα therapeutics: a potency engineered Fc-fusion referred to as Efbalropendekin alfa; a heterodimeric, PD-1 targeted cytokine assessed in non-clinical studies (PD1/IL15 TaCk); and an anti-respiratory syncytial virus targeted cytokine that serves as a non-binding isotype control (RSV/IL15 TaCk)...Finally, we leverage our QSP modeling framework to generate virtual cohorts with various translational scenarios to make clinical PK/PD predictions in response to PD1/IL15 TaCk treatment. Overall, the systems modeling presented herein offers a novel approach to integrate non-clinical datasets, aid in translation, and support dosing decisions for cytokine-based therapies that activate the immune system and display a dynamic PK/PD relationship."

Journal • Oncology • Respiratory Diseases • CD4 • CD8 • IL15

An Open-Label Dose-Escalation Study to Evaluate XmAb24306 as a Single Agent and in Combination With Atezolizumab in Participants With Locally Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1 | N=195 | Active, not recruiting | Sponsor: Genentech, Inc. | Trial completion date: Sep 2025 ➔ Dec 2025 | Trial primary completion date: Sep 2025 ➔ Dec 2025

Trial completion date • Trial primary completion date • Solid Tumor

A Study to Evaluate the Safety, Pharmacokinetics, and Activity of XmAb24306 in Combination With Cevostamab in Participants With Relapsed/Refractory Multiple Myeloma (clinicaltrials.gov) - P1 | N=90 | Active, not recruiting | Sponsor: Genentech, Inc. | Trial primary completion date: Mar 2026 ➔ Sep 2026

Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

Phase 1a/1b dose-escalation study of efbalropendekin alfa (XmAb24306) as single-agent and with atezolizumab in solid tumors (AACR 2025) - "Based on the totality of the data, the RDE for EBA was 0.12 mg/kg Q4W and supported the enrollment of dose-expansion to further assess safety and activity."

P1 data • Oncology • Solid Tumor • CD4 • CD8 • IL15 • IL2

Roche drops HER2 bispecific, Xencor-partnered cytokine from early-phase pipeline (FierceBiotech) - "Roche has given two early-phase bispecifics the heave-ho, ending work on a HER2xCD3 prospect and an IL-15 candidate it picked up from Xencor...The drugmaker removed (PDF) the molecules from its phase 1 pipeline as part of its fourth-quarter clearout. The HER2 asset, known as both RG6194 and runimotamab, was in development in breast cancer....The IL-15 candidate, efbalropendekin alfa, was designed to drive the expansion and activation of T cells and natural killer cells by fusing IL-15 to its alpha receptor and Xencor’s bispecific Fc domain."

Discontinued • Breast Cancer • Multiple Myeloma

A Study to Evaluate the Safety, Pharmacokinetics, and Activity of XmAb24306 in Combination With Cevostamab in Participants With Relapsed/Refractory Multiple Myeloma (clinicaltrials.gov) - P1 | N=90 | Active, not recruiting | Sponsor: Genentech, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Hematological Malignancies • Multiple Myeloma • Oncology

A Study to Evaluate the Safety, Pharmacokinetics, and Activity of XmAb24306 in Combination With Cevostamab in Participants With Relapsed/Refractory Multiple Myeloma (clinicaltrials.gov) - P1 | N=90 | Recruiting | Sponsor: Genentech, Inc. | Trial completion date: Jan 2027 ➔ Sep 2026 | Trial primary completion date: Aug 2026 ➔ Mar 2026

Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

An Open-Label Dose-Escalation Study to Evaluate XmAb24306 as a Single Agent and in Combination With Atezolizumab in Participants With Locally Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1 | N=250 | Active, not recruiting | Sponsor: Genentech, Inc. | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Metastases • Oncology • Solid Tumor

A Study to Evaluate the Safety and Pharmacokinetics of XMAB24306 in Combination With Daratumumab in Participants With Relapsed/Refractory Multiple Myeloma (clinicaltrials.gov) - P1 | N=18 | Completed | Sponsor: Genentech, Inc. | Recruiting ➔ Completed | N=60 ➔ 18 | Trial completion date: Jul 2026 ➔ Jun 2024 | Trial primary completion date: Jan 2026 ➔ Jun 2024

Combination therapy • Enrollment change • Trial completion • Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

Reactive Airway Disease Associated With Necrotic Non-small Cell Lung Cancer (ATS 2024) - "Description of Case: An 81-year-old man with a 30 pack- smoking history and metastatic G12C KRAS non-small cell lung cancer (NSCLC) in a clinical trial of atezolizumab and XmAB24306—an investigational IL-15/IL-15R⍺ cytokine complex—presented with wheezing and worsening cough newly productive of thick, brown, blood-tinged sputum...After evaluation, a course of prednisone and bronchodilator therapy was initiated with significant clinical improvement...This case illustrates how necrotic debris may modulate bronchial hyperresponsiveness and cause reactive airway disease. It is important that RAD is recognized as a potential sequela of cavitary NSCLC."

Allergy • Asthma • Cough • Immunology • Infectious Disease • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pediatrics • Pneumonia • Pulmonary Disease • Respiratory Diseases • Solid Tumor • IL15 • KRAS • TNFA

An Open-Label Dose-Escalation Study to Evaluate XmAb24306 as a Single Agent and in Combination With Atezolizumab in Participants With Locally Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1 | N=250 | Recruiting | Sponsor: Genentech, Inc. | Trial completion date: Jun 2024 ➔ Sep 2025 | Trial primary completion date: Jun 2024 ➔ Sep 2025

Trial completion date • Trial primary completion date • Oncology • Solid Tumor

IL-15/IL-15Rα-Fc fusion protein XmAb24306 potentiates activity of CD3 bispecific antibodies through enhancing T cell expansion. (PubMed, Mol Cancer Ther) - "Activation of human peripheral T cells by cevostamab, an anti-FcRH5/CD3 TDB, or anti-HER2/CD3 TDB resulted in upregulation of IL-2/15Rβ (CD122) receptor subunit in nearly all CD8+ and majority of CD4+ T cells, suggesting that TDB treatment may sensitize T cells to the IL-15. In summary, our results support the hypothesis where the number of tumor infiltrating T cells is rate limiting for the activity of solid tumor targeting TDBs. Upregulation of CD122 by TDB treatment and the observed synergy with XmAb24306 and T cell bispecific antibodies supports clinical evaluation of this novel immunotherapy combination."

Journal • Oncology • Solid Tumor • CD4 • CD8 • IL15 • IL2

Efbalropendekin Alfa enhances human natural killer cell cytotoxicity against tumor cell lines in vitro. (PubMed, Front Immunol) - "Daratumumab (dara), a monoclonal antibody (mAb) that targets CD38 results in antibody-dependent cellular cytotoxicity (ADCC) of both multiple myeloma (MM) cells and NK cells. Because NK cells express CD38, XmAb24306 increases dara-mediated NK cell fratricide, but overall does not negatively impact the ADCC activity against a MM cell line likely due to increased NK cell activity of the surviving cells. These data show that XmAb24306 increases direct and ADCC-mediated human NK cell cytotoxicity in vitro."

IO biomarker • Journal • Preclinical • Tumor cell • Colorectal Cancer • Gastrointestinal Cancer • Hematological Malignancies • Multiple Myeloma • Oncology • Solid Tumor • IL15

An Open-Label Dose-Escalation Study to Evaluate XmAb24306 as a Single Agent and in Combination With Atezolizumab in Participants With Locally Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1 | N=250 | Recruiting | Sponsor: Genentech, Inc. | Phase classification: P1a/1b ➔ P1

Combination therapy • Metastases • Phase classification • Oncology • Solid Tumor

Xencor Reports Third Quarter 2023 Financial Results (Businesswire) - "Pipeline Updates: (i) Efbalropendekin alfa (XmAb306, IL15/IL15Rα-Fc Cytokine): Xencor exercised its right under the Genentech agreement to convert its co-development and sharing of profits and losses on efbalropendekin alfa into a milestone and royalty arrangement without cost-sharing. The Company expects to finalize contract changes before year end; (ii) XmAb541 (CLDN6 x CD3):...Xencor plans to submit an investigational new drug (IND) application by year end."

IND • Licensing / partnership • Oncology

Complex PK-PD of an engineered IL-15/IL-15Rα-Fc fusion protein in cynomolgus monkeys: QSP modeling of lymphocyte dynamics. (PubMed, Eur J Pharm Sci) - "XmAb24306 is a lymphoproliferative interleukin (IL)-15/IL-15 receptor α (IL-15Rα) Fc-fusion protein currently under clinical investigation as an immunotherapeutic agent for cancer treatment...The model is used to predict lymphoid tissue expansion and to simulate PK-PD for different dose regimens. Thus, the model provides insight into the mechanisms underlying the observed PK-PD behavior of an engineered cytokine and can serve as a framework for the rapid integration and analysis of data that emerges from ongoing clinical studies in cancer patients as single-agent or given in combination."

IO biomarker • Journal • PK/PD data • Oncology • CD4 • CD8 • IL15

A Dose-escalation Study to Evaluate the Safety, Pharmacokinetics, and Activity of XmAb24306 in Combination With Cevostamab in Participants With Relapsed/Refractory Multiple Myeloma (clinicaltrials.gov) - P1 | N=90 | Recruiting | Sponsor: Genentech, Inc.

Combination therapy • New P1 trial • Hematological Malignancies • Immune Modulation • Multiple Myeloma • Oncology

Xencor Presents Early Clinical Data from Combination Study of Vudalimab and New Data from Multiple Preclinical-stage XmAb Programs at the SITC Annual Meeting (Businesswire) - "In vitro, B7-H3 x NKG2D and MICA/B x B7H3 NKEs activated NK cells and enhanced NK cell mediated lysis of tumor cells. Additionally, in vitro anti-tumor activity was enhanced when combined with an analog of the proinflammatory IL15-Fc cytokine, XmAb306; Xencor designed a PDL1 x PDL2 x CD28 XmAb trispecific antibody to provide CD28 costimulation in the presence of TCR engagement and either PDL1 or PDL2 antigens...In vitro, the trispecific enhanced the activity of a CD3 bispecific antibody, a modality known to indirectly promote PDL1 and PDL2 expression; Xencor’s LAG-3 x IL-15 candidate molecules demonstrated high selectivity for LAG3-positive cell populations in multiple in vitro and in vivo models. In a preclinical tumor model, a combination of LAG-3 x IL-15 and an anti-PD1 antibody inhibited tumor growth better than anti-PD1 antibody alone."

Preclinical • Hematological Malignancies • Oncology • Solid Tumor

A Study to Evaluate the Safety and Pharmacokinetics of XMAB24306 in Combination With Daratumumab in Participants With Relapsed/Refractory Multiple Myeloma (clinicaltrials.gov) - P1 | N=60 | Recruiting | Sponsor: Genentech, Inc. | Trial primary completion date: Jul 2026 ➔ Jan 2026

Combination therapy • Trial primary completion date • Hematological Malignancies • Immune Modulation • Multiple Myeloma • Oncology

A Study to Evaluate the Safety and Pharmacokinetics of XMAB24306 in Combination With Daratumumab in Participants With Relapsed/Refractory Multiple Myeloma (clinicaltrials.gov) - P1 | N=60 | Recruiting | Sponsor: Genentech, Inc. | Not yet recruiting ➔ Recruiting

Combination therapy • Enrollment open • Hematological Malignancies • Immune Modulation • Multiple Myeloma • Oncology

Xencor to Present Preclinical Data from XmAb Cytokine Programs at the American Association for Cancer Research (AACR) Annual Meeting 2022 (Businesswire) - "Xencor...today announced it will present preclinical data on two novel XmAb® cytokine programs...'We look forward to sharing our first preclinical data from two additional wholly owned cytokine programs, a decoy-resistant and potency-reduced IL18-Fc fusion protein, and a LAG-3 targeted IL15/IL15α-Fc fusion protein, which is biased toward binding and activating checkpoint-upregulated lymphocytes that are more likely to be tumor-reactive.'"

Preclinical • Oncology

A Study to Evaluate the Safety and Pharmacokinetics of XMAB24306 in Combination With Daratumumab in Participants With Relapsed/Refractory Multiple Myeloma (clinicaltrials.gov) - P1 | N=60 | Not yet recruiting | Sponsor: Genentech, Inc.

Combination therapy • New P1 trial • Hematological Malignancies • Immune Modulation • Multiple Myeloma • Oncology

Xencor Presents Data from Multiple Preclinical XmAb Bispecific Antibody Programs and IL-12 Cytokine, XmAb662, at the SITC Annual Meeting (Businesswire) - "IL12 Fc-fusions engineered for reduced potency and extended half-life exhibit strong anti-tumor activity and improved therapeutic index compared to wild-type IL12 agents'...Prior clinical studies have demonstrated IL-12 has significant anti-tumor activity; however, its toxicity has limited its potential. Xencor’s IL-12 program follows the same potency reduction design strategy as the Company’s IL15-Fc fusions in oncology, where reduced potency led to improved pharmacokinetics, pharmacodynamics and safety in preclinical studies. In addition, preliminary clinical data from Xencor’s IL15-Fc program, XmAb306, showed generally good tolerability and robust and sustained immune cell expansion...XmAb662 was selected for further development and demonstrated significant anti-tumor activity in vivo...The Company anticipates submitting an IND application for XmAb662 in 2022."

IND • Preclinical • Oncology

Xencor Reports Third Quarter 2021 Financial Results and Announces Encouraging Preliminary Data from Ongoing Phase 1 Study of Potency-reduced IL15-Fc Cytokine, XmAb306 (Businesswire) - P1, N=250; NCT04250155; Sponsor: Genentech, Inc.; "XmAb306 has been generally well tolerated as both a monotherapy and in combination with atezolizumab....In recently dosed cohorts, the study has reached dose levels that promote T cell activity, and evidence of peripheral effector T cell proliferation has been observed....Significant NK cell expansion and accumulation was observed beginning in lower dose cohorts, and at higher dosing cohorts NK cell expansion has reached 40- to 100-fold higher levels than baseline and has been sustained for weeks throughout dosing. Additional studies of XmAb306 in combination with other agents are being planned."

New trial • P1 data • Oncology • Solid Tumor