Elahere (mirvetuximab soravtansine-gynx)

P3, N=453, Completed, ImmunoGen, Inc. | Active, not recruiting --> Completed

FRα-targeting ADCs, including MIRV, demonstrated definite efficacy and good safety as novel choices for second-line and beyond treatment of advanced or recurrent ovarian cancer. Patients with high FRα expression showed ORR and PFS benefits similar to those in the overall cohort.

P3, N=110, Not yet recruiting, AbbVie

P2, N=18, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Aug 2028 --> May 2027 | Trial primary completion date: Aug 2025 --> Jun 2024

As demonstrated among 682 participants, the safety profile of MIRV is well tolerated and consists primarily of low-grade gastrointestinal, fatigue, headache, peripheral neuropathy, and resolvable ocular adverse events.

P2, N=136, Active, not recruiting, AGO Research GmbH | Recruiting --> Active, not recruiting

Due to the very limited number of NAb-positive individuals, no conclusions could be drawn on the effect of NAb on efficacy. Both the validation tests and the data from the MIRV clinical studies demonstrated that these assays were suitable and reliable for the detection of MIRV ADAs and NAbs. These validated assays will continue to be used to monitor MIRV immunogenicity in future clinical trials.

Introduction Mirvetuximab soravtansine-gynx (MIRV) is an antibody-drug conjugate that binds to folate receptor alpha and delivers a microtubule inhibitor payload...Median PFS did not significantly differ based on number of prior treatment lines (for 1-3 versus >3 lines, P = 0.3) or prior PARP inhibitor ( P = 0.9) or bevacizumab ( P = 0.4) use...Conclusion/Implications MIRV confers meaningful PFS benefit for a subset of individuals. Biomarkers of response and resistance are urgently needed to optimize patient selection for treatment.

97.5% had prior taxanes, 81% prior poly (ADP-ribose) polymerase inhibitors (PARPi) [74.7% of whom progressed while on PARPi], 64.6% prior bevacizumab, 98.8% had 2+ prior lines of therapy, and BRCA status was 27.8% positive, 72.2% negative. MIRV demonstrated notable efficacy in this heavily pretreated PSOC population, including among those who may have PARPi resistance. MIRV continues to demonstrate a differentiated safety profile consisting primarily of low-grade neurosensory, GI, and resolvable ocular AEs. These data position MIRV to become a novel treatment option for patients in ≥3L PSOC with FRα positive expression.

P1, N=86, Active, not recruiting, Shattuck Labs, Inc. | Trial completion date: Apr 2025 --> Nov 2024

The trough concentration of MIRV correlated with efficacy whereas the AUC of MIRV was associated with major AEs. The ER relationships supported the selected therapeutic dose regimen.

P=N/A, N=50, Recruiting, Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital Hainan Hospital; Hangzhou ZhongMei Huadong Pharmaceutical Co., Ltd.

In breast cancer, T-DM1 and T-DXd which is HER2-targeted ADC have been approved and are broadly used in Japan. Sacituzumab govitecan, TROP2-ADC has been approved in US...In gynecological cancers, tisotumab vedotin for cervical cancer and mirvetuximab soravtansine for ovarian cancer have been approved in the US...The current development landscape suggests further enhancement of ADC treatment efficacy through new targets, novel payloads, bispecific ADCs, and combination therapies with immunotherapy. This article outlines the current status of ADCs in breast and gynecological cancers, highlighting ongoing development and challenges emerging in the field.

P2, N=100, Recruiting, ImmunoGen, Inc. | Not yet recruiting --> Recruiting

P2, N=50, Recruiting, Alessandro Santin

P1, N=86, Active, not recruiting, Shattuck Labs, Inc. | Trial primary completion date: Jul 2024 --> Dec 2024

P3, N=453, Active, not recruiting, ImmunoGen, Inc. | Trial completion date: Apr 2024 --> Aug 2024

In FRα-high PSOC, MIRV plus bevacizumab previously showed promising efficacy (objective response rate, 69% [95% CI: 41-89]; median progression-free survival, 13.3 months [95% CI: 8.3-18.3]; median duration of response, 12.9 months [95% CI: 6.5-15.7]) and safety. The Phase III randomized GLORIOSA trial will evaluate MIRV plus bevacizumab vs. bevacizumab alone as maintenance therapy in patients with FRα-high PSOC who did not have disease progression following second-line platinum-based doublet chemotherapy plus bevacizumab.Clinical Trial Registration: ClinicalTrials.gov ID: NCT05445778; GOG.org ID: GOG-3078; ENGOT.ESGO.org ID: ENGOT-ov76.

Mirvetuximab soravtansine-gynx (MIRV) is a folate receptor alpha (FRα) directed antibody and microtubule inhibitor that is approved for patients with FRα positive platinum resistant recurrent epithelial ovarian cancer...It is suspected that most paclitaxel reactions are due to the cremophor solvent rather than paclitaxel itself; however, cross reactivity with docetaxel which is suspended in a polysorbate solution can also occur...MIRV is also suspended in polysorbate and has a similar mechanism to taxanes, therefore it was unknown if a patient with a prior grade 5 reaction to paclitaxel would also have a reaction to MIRV. Though this is one case, patients with a history of severe hypersensitivity to paclitaxel and meet the criteria for MIRV could be treated with MIRV with careful monitoring.

In OC, primary chemotherapy, paclitaxel carboplatin, bevacizumab, and PARP inhibitors have shown prolonged progression-free survival and a favorable overall response rate compared to conventional treatments...Recently, mirvetuximab soravtansine, an alpha-folate receptor (FRα)-targeted antibody-drug conjugate (ADC), was approved by the US Food and Drug Administration for patients with FRα-positive recurrent epithelial OC (EOC)...Ongoing clinical trials are evaluating ADCs targeting FRα and human epidermal growth factor receptor 2, trophoblast cell surface antigen-2, sodium-dependent phosphate transport protein 2B, and cadherin-6 in Phase II/III studies. In this review, we summarize the existing evidence supporting the use of ADCs in OC, discuss ongoing clinical trials and preclinical studies, and explore the potential of these innovative agents to address the challenges in OC treatment.

Here, we report updated nonanalytical results based on a median follow-up of 16.7 months. 453 PROC pts with high FRα expression (VENTANA FOLR1 [FOLR1-2.1] RxDx Assay) with 1-3 prior therapies were randomized 1:1 to MIRV 6 mg/kg, adjusted ideal body weight, Day 1 of a 21-day cycle or ICC: paclitaxel (PAC), pegylated liposomal doxorubicin (PLD), or topotecan (Topo). With a median follow-up of 16.7 months, MIRV demonstrated improved efficacy vs ICC in pts with PROC. The efficacy data, along with the well-characterized safety profile, supports MIRV as the standard of care for pts with FRα positive PROC. Clinical Trial Information: NCT04209855.

97.5% had prior taxanes, 81% prior poly (ADP-ribose) polymerase inhibitors (PARPi) [74.7% of whom progressed while on PARPi], 64.6% prior bevacizumab, 98.8% had 2+ prior lines of therapy, and BRCA status was 27.8% positive, 72.2% negative. MIRV demonstrated clinically meaningful antitumor activity and favorable tolerability in patients with FRα-high PSOC. The efficacy and safety data support the use of MIRV in PSOC patients with ≥ 2 prior platinum-containing regimens or platinum allergy. Clinical Trial: NCT05041257.

Mirvetuximab soravtansine (MIRV), an FRα-targeting antibody-drug conjugate, is active in high-grade serous epithelial ovarian cancer (HGSOC)... FRα was highest in HGSOC and was associated with advanced stage and BRCA status. Sample age, anatomical site, and PFI did not affect FRα expression, suggesting that any sample is suitable for determining FRα status. Variability was observed in cores from the same specimen, which appeared to be driven by tumour heterogeneity versus biological changes.

Future studies of FRα-directed therapy in patients with LGSC are warranted. Discordant FRα status at recurrence suggests potential benefit for retesting. A biomarker-driven approach to direct treatment selection in LGSC is recommended. As high FRα expression is more common amongst tumors lacking MAPK pathway genetic alterations, FRα testing to determine eligibility for mirvetuximab soravtansine therapy is particularly recommended for this subgroup.

Mirvetuximab soravtansine is an antifolate receptor alpha monoclonal antibody, with an approved FOLR1-2.1 immunohistochemical biomarker...Significant differences in FOLR1 staining were noted between histotypes, age of the specimen, type of case tested, and site of disease tested. Further testing is needed to help determine the best tissue to be utilized for this new biomarker.

P2, N=18, Active, not recruiting, Dana-Farber Cancer Institute | Recruiting --> Active, not recruiting | N=35 --> 18 | Trial completion date: Oct 2026 --> Aug 2028 | Trial primary completion date: Oct 2024 --> Aug 2025

These results support the clinically meaningful efficacy of mirvetuximab soravtansine-gynx in FRα-expressing platinum-resistant ovarian cancer, irrespective of prior treatment or sequence.

P1, N=86, Active, not recruiting, Shattuck Labs, Inc. | Enrolling by invitation --> Active, not recruiting

P1/2, N=25, Recruiting, Takeda | Not yet recruiting --> Recruiting

However, identified gaps, including limited diversity in patient populations, sparse quality of life data, and the need for long-term safety information, indicate areas for future research. Exploration of additional biomarkers predicting mirvetuximab soravtansine responsiveness is essential for personalized treatment.

453 PROC pts with high FRα expression (VENTANA FOLR1 [FOLR1-2.1] RxDx Assay) with 1-3 prior therapies were randomized 1:1 to MIRV 6 mg/kg, adjusted ideal body weight, Day 1 of a 21-day cycle or ICC: paclitaxel, pegylated liposomal doxorubicin, or topotecan...In the MIRV arm, 36% had prior bevacizumab vs. 45% in the ICC arm, and 55% had prior PARPi vs 59% in the ICC... Dose modifications occurred at similar rates in both treatment arms. MIRV demonstrated a longer PFS, OS, and higher ORR vs ICC in patients with dose modifications. The efficacy data and the well-characterized safety profile support MIRV as the standard of care for pts with FRα positive PROC.

P2, N=114, Active, not recruiting, ImmunoGen, Inc. | Recruiting --> Active, not recruiting | Trial primary completion date: Jun 2024 --> Jun 2025

P1/2, N=25, Not yet recruiting, Takeda

The median age for the long-term survivor cohort was 63 years; 20% of patients had 1 prior, 41% had 2 priors, 38% had 3 priors, 58% were treated with prior bevacizumab and 33% were treated with prior PARPi. In a pooled analysis of 682 patients, long-term survival was observed in 34% of patients, with a median overall survival of 28.35 months and with 66% and 40% alive at 24 and 30 months, respectively. The observed MIRV tolerability in this patient cohort was generally consistent with the safety profile as reported in the U.S. prescribing information. These data add support to MIRV as a new standard of care for patients with FRα positive PROC.

453 PROC pts with high FRα expression (VENTANA FOLR1 [FOLR1-2.1] RxDx Assay) with 1-3 prior therapies were randomized 1:1 to MIRV 6 mg/kg, adjusted ideal body weight, Day 1 of a 21-day cycle or ICC: paclitaxel, pegylated liposomal doxorubicin, or topotecan...In the MIRV arm, 57% had prior bevacizumab vs. 67% in the ICC arm, and 57% had prior PARPi experience vs. 58% in the ICC arm in pts ≥ 65... MIRV is the first treatment to demonstrate a PFS, ORR, and OS benefit in PROC compared to ICC. MIRV demonstrated a longer PFS, OS, and higher ORR vs ICC in the older population. Importantly, MIRV had fewer dose discontinuations than ICC, suggesting that TEAEs were more manageable The efficacy data and the well-characterized safety profile support MIRV as the standard of care for pts with FRα positive PROC across all ages.

Amongst tumors that had not received mirvetuximab soravtansine, no difference in OS was observed between HG F- v HG F+ (HR 1.3, p = .072; median OS HG F-: 87 months [N = 1092], HG F+: 98 [N = 756])... A notable portion of LG tumors were FOLR1+, which suggests that FOLR1 expression in LG could be a viable target for this rare histology, particularly in the recurrent setting. MAPK activation was significantly higher in LG tumors when compared to HG, yet no difference between LG F+ and F- tumors was observed.

At the current price, MIRV for PROC with high-FRα expression is not the cost-effective strategy in the US. However, its treatment has higher health benefits in bevacizumab-naïve patients, which is likely to be an alternative.

This triplet regimen (MIRV+carboplatin+bevacizumab) was highly active, with a tolerable AE profile in participants with recurrent, platinum-sensitive, FRα-expressing ovarian cancer. Thrombocytopenia was the primary cause of dose modifications. These outcomes compare favorably to historical data reported for platinum-based chemotherapy plus bevacizumab regimens in similar patient populations.

P1, N=44, Completed, City of Hope Medical Center | Active, not recruiting --> Completed

Recently, the FDA approved mirvetuximab soravtansine for platinum-resistant ovarian carcinoma with FOLR1 overexpression, typically high-grade serous carcinoma... To our knowledge, this is the largest study to date of FOLR1 expression in USC. Nearly 1 in 5 USC patients are FOLR1+, independent of HER2 status. Further research testing the efficacy of FOLR1-targeted therapy in USC is needed, as approval could potentially double the proportion of patients with available targeted therapies.

P1/2, N=264, Completed, ImmunoGen, Inc. | Phase classification: P1b/2 --> P1/2

Together, these data showed that the assay is highly reliable, consistently producing evaluable results in the clinical setting. The VENTANA FOLR1 Assay is a robust and reproducible assay for detecting FRα expression and identifying a patient population that derived clinically meaningful benefit from MIRV in the SORAYA study.