XMT-1522 / Mersana - LARVOL DELTA

Emerging new treatments in HER2 positive breast cancer (SG-BCC 2023) - P1 | "Trastuzumab deruxtecan (T-DXd) was approved in December 2022 by the FDA for patients with pretreated HER2- positive breast cancer based on the results of the phase III trial Destiny-Breast03 [3], showing an impressive improvement in progression-free survival with an hazard ratio of 0.33 (95% CI 0.26– 0.43, p-value<0.0001) compared to T-DM1, according to the last update presented at SABCS 2022 [4]...Besides T-DXd and SYD985, other ADCs have been or are under investigation, including, but not limited to, patritumab deruxtecan, disitamab vedotin, XMT-1522, MM-302, MEDI-4276, A166, ARX788, BAT8001 and PF-06804103...Several TKIs have been successfully developed, with tucatinib being the latest to enter clinical practice based on the results of the HER2CLIMB trial [7], with particular importance for patients with brain metastases. Other promising emerging treatments targeting HER2/3 receptors are the HER2- targeted bispecific antibodies (including, among others, KN026..."

IO biomarker • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Immune Modulation • Oncology • Solid Tumor • CDK4 • ER • HER-2 • KLRC1 • PD-L1 • PIK3CA

A phase Ib, first-in-human, dose escalation and expansion study of XMT-1522, a novel antibody-drug conjugate (ADC) directed against HER2, in patients with advanced breast cancer and other advanced tumors expressing HER2. (ASCO 2017) - P1b; "The EXP segment will open at the RP2D and will further assess safety and tolerability of XMT-1522 and assess efficacy in selected patient populations. EXP will enroll 4 cohorts (N = 20 each)."

Biosimilar • Gastric Cancer • HER2 Breast Cancer • Non Small Cell Lung Cancer • Ophthalmology

Phase 1 dose escalation of XMT-1522, a novel HER2-targeting antibody-drug conjugate (ADC), in patients (pts) with HER2-expressing breast, lung and gastric tumors. (ASCO 2018) - P1b; "NCT02952729 Background: XMT-1522 is comprised of 10-15 molecules of the payload AF-HPA, an auristatin-derivative with two-step intra-tumor metabolism intended to optimize therapeutic index, conjugated to a novel anti-HER2 monoclonal antibody via the Dolaflexin ADC platform...The ongoing PR occurred at first assessment in a pt with HER2-positive BC previously treated with ado-trastuzumab emtansine... XMT-1522 has been well-tolerated up to the 21.3 mg/m2 dose level with early signs of anti-tumor activity. Neither MTD nor RP2D has been identified. Dose escalation continues in pts with advanced HER2-expressing BC, GC and NSCLC."

Clinical • P1 data • Gastric Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Non Small Cell Lung Cancer

Messersmith Makes Sense of the Novel Approaches on the Rise in GI Malignancies (OncLive) - "The heterogeneity of tumors in GI cancers continues to pose a challenge, according to Messersmith. As such, understanding how circulating tumor DNA will play into the management of patients as RAS inhibitors emerge in the clinic will be an area of interest going forward, Messersmith added."

Media quote

Study of Antibody Drug Conjugate in Patients With Advanced Breast Cancer Expressing HER2 (clinicaltrials.gov) - P1b; N=120; Completed; Sponsor: Mersana Therapeutics; Active, not recruiting ➔ Completed

Clinical • Trial completion • Breast Cancer • Gastric Cancer • Gastrointestinal Cancer • HER2 Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HER-2

Synergy of an anti-HER2 ADC TAK-522 (XMT-1522) in combination with anti-PD1 monoclonal antibody (mAb) in a syngeneic breast cancer model expressing human HER2 (AACR 2018) - "Treatment in this poorly immunogenic tumor model with TAK-522 but not Kadcyla showed significant inhibition of tumor growth in vivo. TAK-522 is currently being tested in a phase-1b clinical trial in patients with advanced breast, lung and gastric cancer expressing HER2. Based on our data, TAK-522 represents a potential candidate for combination therapies with immune checkpoint modulators in patients with poorly immunogenic HER2 expressing tumors."

Combination therapy • IO Biomarker • PD(L)-1 Biomarker • Preclinical • Gastric Cancer • HER2 Breast Cancer

Antibody-Drug Conjugates in HER2-Positive Breast Cancer (OncLive) - "'Before we had targeted agents against HER2, particularly in the curative setting, it used to be among our most virulent and rapidly fatal of breast cancers,' said...Joyce A. O'Shaughnessy...'It really speaks to the noncross-resistant nature of the deruxtecan and the ability of this agent to really bind and kill cells, even with the low level of HER2 expression,' she said. Some clinicians may also use trastuzumab deruxtecan in patients with a large disease burden or severe diseaserelated symptoms, according to O'Shaughnessy."

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Antibody-Drug Conjugates in Breast Cancer: a Comprehensive Review. (PubMed, Curr Treat Options Oncol) - "In breast cancer, the early success of trastuzumab-emtansine (T-DM1) in the HER2-positive metastatic setting led to great hopes, later dashed by results in the early setting (KRISTINE trial) and in combination with pertuzumab (MARIANNE trial). Parallel to this, development of ADCs in breast cancer has suffered other setbacks, including the recent failure of other agents (MM-302) as well as the suspension of a few programs (XMT-1522, ADCT-502) with the overall effect of dampening the impetus of this concept and halting/delaying the progress of drugs associated with it, particularly when immunotherapy is at the center of so many efforts...Finally, breakthroughs are occurring in the orphan triple-negative breast cancer subtype with agents targeting surface proteins. The recent results of Sacituzumab govitecan suggest substantial activity in heavily pre-treated patients and underscore the enduring relevance of antibody drug conjugates as a path towards better outcomes."

Journal • Review • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Immune Modulation • Inflammation • Oncology • Solid Tumor • Triple Negative Breast Cancer

A Novel Anti-HER2 Antibody-Drug Conjugate XMT-1522 for HER2-Positive Breast And Gastric Cancers Resistant to Trastuzumab Emtansine. (PubMed, Mol Cancer Ther) - "We conclude that XMT-1522 was effective in HER2-positive breast cancer and gastric cancer cell lines resistant to T-DM1, and in xenograft models resistant to T-DM1. The results support the testing of XMT-1522 in clinical trials in patients with HER2-positive cancer."

Journal • Breast Cancer • Gastric Cancer • Gastrointestinal Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor

Study of Antibody Drug Conjugate in Patients With Advanced Breast Cancer Expressing HER2 (clinicaltrials.gov) - P1b; N=120; Recruiting; Sponsor: Mersana Therapeutics; Not yet recruiting ➔ Recruiting

Enrollment open • Biosimilar • Breast Cancer • Gastric Cancer • Gastrointestinal Cancer • HER2 Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology

Simultaneous quantification of total antibody and antibody-conjugated drug for XMT-1522 in human plasma using immunocapture-liquid chromatography/mass spectrometry. (PubMed, J Pharm Biomed Anal) - "The intra- and inter-day precision and accuracy were well within 15%. The validated method, with the characteristics of high efficiency, great selectivity, free of carryover, short LC-MS/MS time (˜3.5 min) and low sample volume (20 μl), was successfully applied for analyzing Phase 1 cancer patient samples."

Journal

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

Mersana Therapeutics Announces Fourth Quarter and Full Year 2018 Financial Results and Provides Business Updates (GlobeNewswire, Mersana Therapeutics, Inc.) - "The Company is planning to report data from the dose escalation portion of the [Phase 1] study...of XMT-1536 for the treatment of NaPi2b-expressing cancers...in the second quarter of 2019...Associated with the discontinuation of the XMT-1522 program, the Company expects to recognize remaining deferred revenue under ASC 606 in the first quarter of 2019 to reflect termination of the Takeda agreement. Mersana announced the discontinuation of the development of XMT-1522 due to the competitive landscape and to prioritize its resources on advancing XMT-1536."

Discontinuation • P1 data

Study of Antibody Drug Conjugate in Patients With Advanced Breast Cancer Expressing HER2 (clinicaltrials.gov) - P1b; N=120; Active, not recruiting; Sponsor: Mersana Therapeutics; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed