DHES0815A / Roche - LARVOL DELTA

The HER2-directed antibody-drug conjugate DHES0815A in advanced and/or metastatic breast cancer: preclinical characterization and phase 1 trial results. (PubMed, Nat Commun) - P1 | "Approved antibody-drug conjugates (ADCs) for HER2-positive breast cancer include trastuzumab emtansine and trastuzumab deruxtecan. To develop a differentiated HER2 ADC, we chose an antibody that does not compete with trastuzumab or pertuzumab for binding, conjugated to a reduced potency PBD (pyrrolobenzodiazepine) dimer payload...A dose-escalation study (ClinicalTrials.gov: NCT03451162) in patients with HER2-positive metastatic breast cancer, with the primary objective of evaluating the safety and tolerability of DHES0815A and secondary objectives of characterizing the pharmacokinetics, objective response rate, duration of response, and formation of anti-DHES0815A antibodies, is reported herein. Despite early signs of anti-tumor activity, patients at higher doses develop persistent, non-resolvable dermal, ocular, and pulmonary toxicities, which led to early termination of the phase 1 trial."

Journal • Metastases • P1 data • Preclinical • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2

The HER2-directed antibody-drug conjugate DHES0815A in advanced and/or metastatic breast cancer: preclinical characterization and phase 1 trial results (Nature, Nat Commun) - P1 | N=14 | NCT03451162 | Sponsor: Genentech, Inc | "Out of 14 evaluable patients, one patient (7%) dosed at 1.2 mg/kg experienced a confirmed complete response after 6 cycles according to RECIST v1.134. Two patients achieved a partial response (14%), eight patients (57%) showed a confirmed best response of stable disease, two had progressive disease (14%) and one patient was not considered evaluable by the investigator (7%). The median duration of treatment was 64 days (43–62), and the patient achieving complete response remained on study for 32 months....Despite promising anti-tumor activity, the severity, persistence, and non-resolvable nature of the toxicities compelled the decision to discontinue this phase 1 trial. Due to the limited responses at doses <4.0 mg/kg (1 patient at 1.2 mg/kg), it was deemed unlikely to identify a dose with sufficient efficacy and safety to warrant additional development in the clinic."

Discontinued • P1 data • Trial termination • HER2 Positive Breast Cancer

The HER2-directed antibody-drug conjugate DHES0815A in advanced and/or metastatic breast cancer: preclinical characterization and phase 1 trial results (Nature, Nat Commun) - P1 | N=14 | NCT03451162 | Sponsor: Genentech, Inc | "Out of 14 evaluable patients, one patient (7%) dosed at 1.2 mg/kg experienced a confirmed complete response after 6 cycles according to RECIST v1.134. Two patients achieved a partial response (14%), eight patients (57%) showed a confirmed best response of stable disease, two had progressive disease (14%) and one patient was not considered evaluable by the investigator (7%). The median duration of treatment was 64 days (43–62), and the patient achieving complete response remained on study for 32 months....Despite promising anti-tumor activity, the severity, persistence, and non-resolvable nature of the toxicities compelled the decision to discontinue this phase 1 trial. Due to the limited responses at doses <4.0 mg/kg (1 patient at 1.2 mg/kg), it was deemed unlikely to identify a dose with sufficient efficacy and safety to warrant additional development in the clinic."

Discontinued • P1 data • Trial termination • HER2 Positive Breast Cancer

The HER2-directed antibody-drug conjugate DHES0815A in advanced and/or metastatic breast cancer: preclinical characterization and phase 1 trial results (Nature, Nat Commun) - "In nonclinical models, DHES0815A demonstrates anti-tumor efficacy in HER2+ models of breast and gastric cancer, including models insensitive to T-DM1. These non-clinical data present a viable rationale to explore the pharmacokinetics, safety, and tolerability for preliminary assessment of anti-tumor activity of DHES0815A in patients with HER2+ mBC....Dose-dependent tumor growth inhibition was demonstrated in the HER2+ (IHC 3+ ) breast cancer models MMTV-HER2 Fo5, HCC1569 X2 cell line and WHIM8 PDX model (Fig. 4a), as well as in HER2+ (IHC 3+ ) gastric cancer PDX models STO410 and STO41 (Fig. 4b, see Supplementary Fig. 12 for HER2 IHC for these models)."

Preclinical • Gastric Cancer • HER2 Positive Breast Cancer

The HER2-directed antibody-drug conjugate DHES0815A in advanced and/or metastatic breast cancer: preclinical characterization and phase 1 trial results (Nature, Nat Commun) - "In nonclinical models, DHES0815A demonstrates anti-tumor efficacy in HER2+ models of breast and gastric cancer, including models insensitive to T-DM1. These non-clinical data present a viable rationale to explore the pharmacokinetics, safety, and tolerability for preliminary assessment of anti-tumor activity of DHES0815A in patients with HER2+ mBC....Dose-dependent tumor growth inhibition was demonstrated in the HER2+ (IHC 3+ ) breast cancer models MMTV-HER2 Fo5, HCC1569 X2 cell line and WHIM8 PDX model (Fig. 4a), as well as in HER2+ (IHC 3+ ) gastric cancer PDX models STO410 and STO41 (Fig. 4b, see Supplementary Fig. 12 for HER2 IHC for these models)."

Preclinical • Gastric Cancer • HER2 Positive Breast Cancer

A phase I dose-escalation study of DHES0815A, a HER2-targeting antibody-drug conjugate with a DNA monoalkylator payload, in patients with HER2-positive breast cancer (SABCS 2021) - P1 | "The reduced potency of PBD-MA compared to PBD dimers and the stability of the conjugation site and linker were designed to improve tolerability, whereas the binding of the mAb to a HER2 epitope distinct from trastuzumab and pertuzumab was designed to enable combination therapy with existing HER2 therapies. Despite some anti-tumor activity observed with DHES0815A, development in HER2-positive BC has been discontinued due to safety concerns and the narrow therapeutic window. Toxicities observed in skin, lung, and eyes are clinically apparent only after repeated dose administration. If future exploration of PBD-MA-based constructs is performed in the clinic, close monitoring for delayed toxicities is warranted."

Clinical • P1 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor

Challenges in Developing PBD-Based ADCs: Early Development Results of a HER2 ADC Containing a Reduced Potency PBD Dimer Conjugated to a Novel HER2 Antibody (PEGS 2022) - "The HNSTD in cynomolgus monkey was 12 mg/kg. Preclinical efficacy and safety data and Phase 1 results in HER2+ BC for DHES0815A will be presented."

Breast Cancer • Gastric Cancer • Gastrointestinal Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2

Preclinical development of DHES0815A: A HER2-directed antibody-drug conjugate comprised of a reduced potency PBD dimer linked to a domain I binding HER2 antibody (SABCS 2021) - "DHES0815A was more potent than T-DM1 in HER2-positive and HER2-low breast and gastric cancer PDX models and demonstrated combination activity with standard of care agents T-DM1 or docetaxel. DHES0815A is a HER2-directed ADC comprised of a domain I binding antibody linked to a reduced potency PBD dimer, PBD-MA, via a reducible disulfide linker. The antibody does not interfere with trastuzumab or pertuzumab binding, allowing combination with existing HER2 therapies. The reduced potency payload allows dosing in the linear PK range, supporting our hypothesis."

Preclinical • Breast Cancer • Gastric Cancer • Gastrointestinal Cancer • HER2 Positive Breast Cancer • Oncology • CHEK2

DHES0815A, a novel antibody-drug conjugate targeting HER2/neu, is highly active against uterine serous carcinomas in vitro and in vivo. (PubMed, Gynecol Oncol) - "DHES0815A is both highly selective and toxic to USC tumors overexpressing HER2/neu both in vitro and in vivo. HER2-directed ADCs, alone or in combination with other HER2/neu targeted agents may represent a novel treatment option for patients with tumors harboring HER2/neu overexpression refractory to trastuzumab and traditional chemotherapy."

Journal • Preclinical • Endometrial Cancer • Endometrial Serous Adenocarcinoma • Oncology • Solid Tumor • Uterine Cancer • HER-2

Safety, Tolerability, and Pharmacokinetic (PK) Study of DHES0815A in Participants With Human Epidermal Growth Factor Receptor (HER)2-Positive Breast Cancer (clinicaltrials.gov) - P1; N=14; Completed; Sponsor: Genentech, Inc.; Active, not recruiting ➔ Completed; Trial completion date: Apr 2022 ➔ Jun 2021; Trial primary completion date: Apr 2022 ➔ Jun 2021

Clinical • Trial completion • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2

DHES0815A, a Novel Antibody-Drug Conjugate Targeting HER2/neu, Is Highly Active Against Uterine Serous Carcinomas In Vitro and In Vivo. (SRI 2021) - No abstract available.

Preclinical

[VIRTUAL] In vitro and in vivo activity of DHES0815A, an antibody-drug conjugate targeting HER2/neu in uterine serous carcinoma (AACR 2021) - "DHES0815A is a novel antibody-drug-conjugate (ADC) which binds specifically to HER2 overexpressing tumors at a distinct epitope from that bound by trastuzumab and pertuzumab after which it delivers the toxic payload, PBD-MA, a DNA mono-alkylating agent. DHES0815A is both highly selective and toxic to USC tumors overexpressing HER2/neu both in vitro and in vivo. HER2-directed ADCs, alone or in combination with other HER2/neu targeted agents may represent a novel treatment option for patients with tumors harboring HER2/neu overexpression refractory to trastuzumab and traditional chemotherapy."

Preclinical • Endometrial Cancer • Endometrial Serous Adenocarcinoma • Oncology • Solid Tumor • Uterine Cancer • HER-2

[VIRTUAL] In vitro and in vivo activity of DHES0815A, an antibody-drug conjugate targeting HER2/neu in uterine serous carcinoma (SGO 2021) - No abstract available

Preclinical • Endometrial Serous Adenocarcinoma • Oncology • Uterine Cancer • HER-2

Safety, Tolerability, and Pharmacokinetic (PK) Study of DHES0815A in Participants With Human Epidermal Growth Factor Receptor (HER)2-Positive Breast Cancer (clinicaltrials.gov) - P1; N=14; Active, not recruiting; Sponsor: Genentech, Inc.; Trial completion date: Apr 2020 ➔ Apr 2022; Trial primary completion date: Apr 2020 ➔ Apr 2022

Clinical • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2

Safety, Tolerability, and Pharmacokinetic (PK) Study of DHES0815A in Participants With Human Epidermal Growth Factor Receptor (HER)2-Positive Breast Cancer (clinicaltrials.gov) - P1; N=14; Active, not recruiting; Sponsor: Genentech, Inc.; Trial completion date: Jan 2022 ➔ Apr 2020; Trial primary completion date: Jan 2022 ➔ Apr 2020

Clinical • Trial completion date • Trial primary completion date • HER-2

Safety, Tolerability, and Pharmacokinetic (PK) Study of DHES0815A in Participants With Human Epidermal Growth Factor Receptor (HER)2-Positive Breast Cancer (clinicaltrials.gov) - P1; N=14; Active, not recruiting; Sponsor: Genentech, Inc.; N=55 ➔ 14

Clinical • Enrollment change

"Roche Her2 domination under threat? $AZN trastuzumab deruxtecan filed, with huge sellside forecasts. $SGEN tucatinib scores today. $RHHBY discontinued RG6148 last week." (@JacobPlieth)

"$RHHBY discontinuations: RG6109 undiscl ADC; RG6123 anti-CEA MAb; RG6146 bromodomain inh; RG6148 undisclosed (Her2+ breast cancer); RG7625 cathepsin S inh" (@JacobPlieth)

"Did Roche give reason for discontinuation of RG6148 (DHES0815A), anti-HER2/PBD-MA ADC? PBD payload too toxic?" (@jq1234t)

"Anyone know the mechanisms of RG6109 and/or RG6148? $RHHBY" (@JacobPlieth)

Safety, Tolerability, and Pharmacokinetic (PK) Study of DHES0815A in Participants With Human Epidermal Growth Factor Receptor (HER)2-Positive Breast Cancer (clinicaltrials.gov) - P1; N=55; Active, not recruiting; Sponsor: Genentech, Inc.; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed

HER2 Directed Antibody-Drug-Conjugates beyond T-DM1 in Breast Cancer. (PubMed, Int J Mol Sci) - "Currently, several HER2 directed antibody-drug conjugates are under clinical investigation for HER2 amplified but also HER2 expressing but not amplified breast tumors. In this article, we review the current preclinical and clinical evidence of the investigational drugs A166, ALT-P7, ARX788, DHES0815A, DS-8201a, RC48, SYD985, MEDI4276 and XMT-1522."

Journal • Review