upifitamab rilsodotin (XMT-1536) / Mersana, Recepta - LARVOL DELTA

Therapeutic Applications and Target Strategies of Antibody-Drug Conjugates in Ovarian Cancer. (PubMed, Iran J Pharm Res) - "This review summarizes a range of ADCs targeting tumor-associated antigens in ovarian cancer, including mirvetuximab soravtansine (MIRV), trastuzumab deruxtecan (T-DXd), datopotamab deruxtecan (Dato-DXd), sacituzumab tirumotecan (SKB-264), PF-06664178, anetumab ravtansine (BAY 94-9343), BMS-986148, DMOT4039A, RC88, lifastuzumab vedotin (DNIB0600A), upifitamab rilsodotin (ABBV-181), ZW220, DMUC4064A, and sofituzumab vedotin (DMUC5754A). The ADCs hold significant potential to reshape the treatment landscape for ovarian cancer by providing targeted therapeutic options. Further research is required to optimize patient selection, address resistance mechanisms, and improve safety profiles."

Journal • Review • Oncology • Ovarian Cancer • Solid Tumor • MUC4

Antibody-drug conjugates in gynecologic cancer: current landscape, clinical data, and emerging targets. (PubMed, Int J Gynecol Cancer) - "Currently, mirvetuximab soravtansine and tisotumab vedotin have been approved by the Food and Drug Administration for the treatment of folate receptor-alpha-positive, platinum-resistant ovarian cancer and recurrent cervical cancer, respectively, exhibiting promising objective response rates and manageable toxicity profiles in pivotal clinical trials...Additionally, multiple investigational ADCs, such as upifitamab rilsodotin (targeting NaPi2b), trastuzumab deruxtecan (targeting HER2), and sacituzumab govitecan (targeting trophoblast cell surface antigen 2), have demonstrated preliminary efficacy in ongoing clinical trials, offering new therapeutic opportunities for gynecologic malignancies. This review comprehensively summarizes the current clinical applications and research progress of ADCs in gynecologic cancers, including key clinical trials, therapeutic efficacy, safety profiles, and associated challenges. Furthermore, we discuss future optimization strategies,..."

Clinical data • Journal • Review • Cervical Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Pain • Solid Tumor • FOLR1 • HER-2 • SLC34A2

PBPK Modeling to Predict Clinical Drug-Drug Interaction and Impact of Hepatic Impairment for an ADC With the Payload Auristatin F-Hydroxypropylamide. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "Upifitamab rilsodotin-an antibody drug conjugate (ADC)-comprises a NaPi2b-targeted antibody conjugated to an auristatin-based payload (auristatin F-hydroxypropylamide [AF-HPA])...Simulations also showed ~30% increase in unconjugated AF-HPA exposure following an IV dose of 36 mg/m2 in the presence of itraconazole, an inhibitor of both CYP3A4 and P-gp...The model predicted a ~1.5-fold increase in unconjugated AF-HPA AUC and negligible change in the Cmax in patients with moderate and severe hepatic impairment. Finally, this PBPK model may be applied (with modification to the conjugated drug sub-model parameters) to predict DDI and hepatic impairment potential for other ADCs with the same linker and payload."

Journal • Hepatology • CYP3A4 • CYP3A5 • SLC34A2

ADRX-0134 as a novel auristatin-based NaPi2b antibody-drug conjugate with widened therapeutic window (AACR 2025) - "Based on this differential expression profile, a proof-of-concept for an antibody-drug conjugate (ADC) approach utilizing NaPi2b was achieved with lifastuzumab vedotin and upifitamab rilsodotin. Here, the stable TK profile ensured minimal and recoverable hematology findings, an unchanged clinical chemistry profile and normal histology of lung, liver, GI and eye, which were key safety liabilities for other NaPi2b ADCs. In summary, ADRX-0134 exhibits excellent biophysical features with highly selective and increased efficacy in NaPi2b-expressing tumors, while being well-tolerated in cynomolgus monkeys at doses that are expected to provide a widened therapeutic window over first-generation NaPi2b ADCs."

Endometrial Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • SLC34A2

UPGRADE: PHASE 1 TRIAL OF THE NAPI2B-DIRECTED DOLAFLEXIN ANTIBODY DRUG CONJUGATE UPRI IN COMBINATION WITH CARBOPLATIN IN PATIENTS WITH PLATINUM-SENSITIVE OVARIAN CANCER (PSOC) (IGCS 2024) - "15 pts enrolled at UpRi dose levels 20-36 mg/m2. DLTs assessed during cycle 1. One DLT observed (20 mg/m2; G3 AKI due to dehydration)."

Clinical • Combination therapy • P1 data • Oncology • Ovarian Cancer • Solid Tumor • SLC34A2

Mersana Therapeutics Provides Business Update and Announces Second Quarter 2024 Financial Results (GlobeNewswire) - "XMT-2056: Mersana continues to enroll patients in the dose escalation portion of its Phase 1 clinical trial of XMT-2056, the company’s lead Immunosynthen ADC candidate targeting a novel HER2 epitope....Research and development (R&D) expenses for the second quarter of 2024 were $17.2 million, compared to $49.0 million for the same period in 2023. Included in R&D expenses for the second quarter of 2024 were $2.4 million in non-cash stock-based compensation expenses. The year-over-year decline in R&D expenses was primarily related to reduced costs associated with manufacturing and clinical activities for UpRi, a discontinued ADC candidate..."

Commercial • Trial status • Breast Cancer • Colorectal Cancer • Gastric Cancer • Gastrointestinal Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

First-in-Human Dose Escalation Study of XMT-1536 in Cancers Likely to Express NaPi2b (clinicaltrials.gov) - P1 | N=62 | Completed | Sponsor: Mersana Therapeutics

New P1 trial • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor

First-in-Human Dose Expansion Study of XMT-1536 in Cancers Likely to Express NaPi2b (clinicaltrials.gov) - P1 | N=142 | Completed | Sponsor: Mersana Therapeutics

New P1 trial • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor

Targeting NaPi2b with a novel dual TOP1i ADC that shows excellent biophysical properties and high efficacy in vivo (AACR 2024) - "In in vitro assays on various target-positive cell lines with different NaPi2b expression levels, the Araris ADC demonstrated nM-potency in cell cytotoxicity assays, similar to the clinical NaPi2b ADCs lifastuzumab vedotin and upifitamab rilsodotin but being much less toxic to target-negative cells. We believe that this concept in combination with a stable payload attachment at low DAR and an excellent exposure may help to develop ADCs with an improved therapeutic index for various solid tumor indications. The initial results indicate that this ADC may overcome the limitations of current clinical programs against NaPi2b and has the potential to be a first-in-class ADC."

Late-breaking abstract • Preclinical • Oncology • Solid Tumor • SLC34A2

The impact of scaffold, linker, homogeneity and payload selection on the efficacy and tolerability of anti-tubulin ADCs (AACR 2024) - "Two anti-NaPi2b ADCs were produced using two different platforms, XMT-1536 (Dolaflexin platform) and XMT-1592 (Dolasynthen platform), conjugated to the same antibody and employing the same payload. The Dolasynthen platform was deliberately designed, taking into account preclinical and clinical learnings from earlier ADC platforms, to improve both safety and efficacy. In addition, comparisons to clinically approved anti-tubulin ADC platforms are made to provide further context."

Clinical • Oncology • SLC34A2

Journey Ends for Upifitamab Rilsodotin in NaPi2b+ Platinum-Resistant Ovarian Cancer (OncLive) - P1/2 | N=523 | UPLIFT (NCT03319628) | Sponsor: Mersana Therapeutics | "Results from the trial were presented during the 2024 SGO Annual Meeting on Women’s Cancer, and showed that upifitamab rilsodotin produced an ORR of 15.6% (95% CI, 10.0%-22.7%) in those with NaPi2b-positive disease (n = 141); it was 10.2% (95% CI, 5.6%-16.9%) in those with NaPi2b-low disease (n = 127). In the intention-to-treat population (n = 268), the ORR was 13.1% (95% CI, 9.3%-17.7%). These data suggest that the presence of NaPi2b does not enrich for response."

P1/2 data • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor

UPLIFT (ENGOT-OV67/GOG-3048): Results from the phase II trial of upifitamab rilsodotin (UpRi; XMT-1536), a NaPi2b-directed dolaflexin antibody-drug conjugate in platinum-resistant ovarian cancer (SGO 2024) - "Additionally, 84% of patients received prior bevacizumab, 69% received prior PARPi. ILD/pneumonitis reported in 9.7% (Gr3 0.7%). Serious treatment emergent bleeding events were observed, including five G5 (fatal) events."

Late-breaking abstract • P2 data • Oncology • Ovarian Cancer • Solid Tumor • SLC34A2

UPLIFT (ENGOT-Ov67/GOG-3048): Results From The Phase 2 Trial Of Upifitamab Rilsodotin (UpRi; XMT-1536), A NaPi2b-Directed Dolaflexin Antibody-Drug Conjugate (ADC) In Platinum-Resistant Ovarian Cancer (PROC) (ESGO 2024) - "Additionally, 84% of patients received prior bevacizumab, 69% received prior PARPi. Serious treatment emergent bleeding events were observed, including five G5 events. Conclusion In this single-arm open label trial, ORR in the NaPi2b-positive and overall population did not show meaningful improvement compared to historical single-agent chemotherapy, though durable responses were observed."

Late-breaking abstract • P2 data • Oncology • Ovarian Cancer • Solid Tumor • SLC34A2

UPLIFT (ENGOT-ov67/GOG-3048): Results from the phase II trial of upifitamab rilsodotin, a NaPi2b-directed dolaflexin antibody-drug conjugate, in platinum-resistant ovarian cancer (SGO 2024) - P2 | "nab-Sirolimus is an albumin-bound mTOR inhibitor that inhibits the mTOR pathway and has improved intra-tumoral drug accumulation, increased mTOR inhibition and antitumor activity, and longer animal survival compared with oral mTOR inhibitors in preclinical studies. Collaboration with leading NGS vendors is expediting the identification of patients with qualifying TSC1 and TSC2 mutations; ongoing study access is facilitated through a just-in-time approach to trial location activation. Patients with gynecological cancers with TSC1 and TSC2 inactivating alterations are eligible to enroll."

P2 data • Cervical Cancer • Colorectal Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • Uterine Cancer • SLC34A2 • TSC1 • TSC2

Mersana Therapeutics Provides Business Update and Announces Fourth Quarter and Full Year 2023 Financial Results (GlobeNewswire) - "At the European Society of Gynaecological Oncology (ESGO) 2024 Congress from March 7-10, 2024 in Barcelona, Spain, clinical data will be presented for Mersana’s two discontinued NaPi2b ADC product candidates: XMT-1536 (UpRi), which was developed using the company’s first-generation Dolaflexin ADC platform, and XMT-1592, which was developed using the company’s next-generation Dolasynthen ADC platform....The decline in R&D expenses was primarily related to reduced manufacturing and clinical costs related to UpRi and XMT-2056 and manufacturing costs for the company’s Dolasynthen platform, partially offset by increased clinical costs related to XMT-1660."

Clinical data • Commercial • Oncology • Solid Tumor

Mersana Therapeutics Announces Business Updates, Expected 2024 Milestones and Upcoming Presentation at the 42nd Annual J.P. Morgan Healthcare Conference (GlobeNewswire) - "XMT-1660: Mersana continues to advance its Phase 1 clinical trial of XMT-1660, the company’s lead Dolasynthen ADC candidate targeting B7-H4...Mersana plans to initiate tumor-specific expansion cohorts in the second quarter of 2024 and share initial dose escalation and backfill cohort data in mid-2024...XMT-2056: Mersana is restarting its Phase 1 clinical trial of XMT-2056...The company plans to advance dose escalation in 2024....In the first half of 2024, Mersana expects to present data at multiple scientific meetings demonstrating Dolasynthen’s differentiation from first-generation cytotoxic ADC platforms. The presentations will include clinical data from two discontinued ADC candidates, XMT-1592 and XMT-1536 (UpRi)."

Clinical data • P1 data • Trial status • Oncology • Solid Tumor

Uplift: First-in-Human Study of XMT-1536 in Cancers Likely to Express NaPi2b (clinicaltrials.gov) - P1/2 | N=523 | Active, not recruiting | Sponsor: Mersana Therapeutics | Recruiting ➔ Active, not recruiting | Phase classification: P1b/2 ➔ P1/2

Enrollment closed • Phase classification • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • SLC34A2

Upifitamab Rilsodotin Maintenance in Platinum-Sensitive Recurrent Ovarian Cancer (UP-NEXT) (clinicaltrials.gov) - P3 | N=20 | Terminated | Sponsor: Mersana Therapeutics | N=350 ➔ 20 | Trial completion date: Mar 2025 ➔ Sep 2023 | Active, not recruiting ➔ Terminated | Trial primary completion date: Sep 2024 ➔ Sep 2023; Study Terminated by Sponsor

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Peritoneal Cancer • Solid Tumor • BRCA • SLC34A2

UPGRADE: Study of Upifitamab Rilsodotin in Combination With Carboplatin in Participants With High-grade Serous Ovarian Cancer (clinicaltrials.gov) - P1 | N=31 | Terminated | Sponsor: Mersana Therapeutics | N=48 ➔ 31 | Trial completion date: Mar 2025 ➔ Oct 2023 | Active, not recruiting ➔ Terminated | Trial primary completion date: Nov 2024 ➔ Oct 2023; Study Terminated by Sponsor

Combination therapy • Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • SLC34A2

Mersana Therapeutics Announces Topline Data from UPLIFT Clinical Trial in Patients with Platinum-Resistant Ovarian Cancer and Strategic Reprioritization (GlobeNewswire) - P1b/2 | N=444 | UPLIFT (NCT03319628) | Sponsor: Mersana Therapeutics | "Mersana Therapeutics, Inc...today announced that the UPLIFT clinical trial of upifitamab rilsodotin (UpRi) did not meet its primary endpoint....UPLIFT enrolled a total of 268 patients, 141 of whom were determined to be NaPi2b positive....Mersana’s restructuring plan includes a wind-down of UpRi-related development activities, including its UP-NEXT and UPGRADE-A clinical trials and the company’s regulatory and commercial readiness efforts. If analyses of data enable the identification of a path forward for UpRi, the company will consider strategic alternatives for the asset, including partnering."

Discontinued • P1/2 data • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor

UP-NEXT (ENGOT-Ov71-NSGO-CTU/GOG-3049): A Study Of Upifitamab Rilsodotin (UpRi), A NaPi2b-Directed Antibody Drug Conjugate (ADC) In Platinum-Sensitive Recurrent Ovarian Cancer (ESGO 2023) - No abstract available

Oncology • Ovarian Cancer • Solid Tumor • SLC34A2

MODULE 3: Novel Agents and Strategies Under Investigation for Advanced OC (ASCO 2023) - "This activity is supported by educational grants from AstraZeneca Pharmaceuticals LP, GSK, Merck, Mersana Therapeutics Inc, and Novocure Inc. Biological rationale for combining PARP inhibitors with immune checkpoint inhibitors for patients with advanced OC Emerging results from the Phase III DUO-O study of up-front durvalumab in combination with chemotherapy and bevacizumab followed by durvalumab, olaparib and bevacizumab as maintenance therapy; implications for clinical practice and ongoing research Other ongoing Phase III trials investigating the utility of front-line PARP inhibitors with immunotherapy for advanced OC (eg, ATHENA-COMBO, FIRST) Biological rationale for targeting the sodium-dependent phosphate transport protein NaPi2b in OC; mechanism of action of upifitamab rilsodotin (UpRi) Available efficacy and safety data with and ongoing investigation of UpRi for patients with OC Mechanism of action of tumor treating fields and biological rationale for their..."

Metastases • Immune Modulation • Oncology • SLC34A2

UPGRADE: Study of Upifitamab Rilsodotin in Combination With Carboplatin in Participants With High-grade Serous Ovarian Cancer (clinicaltrials.gov) - P1 | N=48 | Active, not recruiting | Sponsor: Mersana Therapeutics | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • SLC34A2

Upifitamab Rilsodotin Maintenance in Platinum-Sensitive Recurrent Ovarian Cancer (UP-NEXT) (clinicaltrials.gov) - P3 | N=350 | Active, not recruiting | Sponsor: Mersana Therapeutics | Recruiting ➔ Active, not recruiting

Enrollment closed • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Peritoneal Cancer • Solid Tumor • BRCA • SLC34A2

Mersana sheds 60% on FDA partial hold on trials for lead asset (SeekingAlpha) - "Mersana Therapeutics...lost ~60% pre-market Thursday after announcing that the FDA issued a partial clinical hold halting the enrollment in its UP-NEXT and UPGRADE-A trials for lead asset UpRi in platinum-sensitive ovarian cancer."

Stock price • Trial suspension • Fallopian Tube Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Peritoneal Cancer • Solid Tumor