4516 Background: Zele is a highly selective Bicycle Drug Conjugate (BDC) targeting Nectin-4, a protein overexpressed in la/mUC. There remains an unmet need in la/mUC for safer and more tolerable treatments. Here, we report an interim analysis (IA) for zele + pembrolizumab (pembro) dosage selection from the Phase 2/3 Duravelo-2 study (NCT06225596/BT8009-230) in previously untreated (untx) pts with la/mUC. Methods: Adults with la/mUC were enrolled into 2 cohorts: previously untx pts eligible for platinum-based chemotherapy (Cohort [Co]1) or pts with ≥1 prior systemic therapy (Co2). IA was conducted to determine the optimized dosage of zele + pembro (Co1) or zele monotherapy (Co2). Herein, we report IA results from Co1. Pts in Co1 were randomized 1:1:1 to: zele 5 mg/m 2 on Days [D]1/8/15 + pembro 200 mg on D1; or zele 6 mg/m 2 on D1/8 + pembro 200 mg on D1; or gemcitabine + cisplatin/carboplatin ± avelumab on a 21-D cycle. Dosage optimization included safety, efficacy, and pharmacokinetic data in pharmacometric and utility score analyses to quantify benefit-risk. Results: IA was performed at 27 weeks of follow-up (N=30 each zele dose group). Median zele treatment (tx) duration was 6.21 months. Confirmed ORRs by BICR among randomized, dosed pts with measurable disease at baseline were 55% (16/29; 7 complete responses [CR], 9 partial responses [PR]; 95% CI 35.7–73.6) and 58% (15/26; 8 CR, 7 PR; 95% CI 36.9–76.6) with zele 5 mg/m 2 and 6 mg/m 2 , respectively. Zele-related adverse events (AEs) were reported in 97% (47% Gr ≥3) of pts at 5 mg/m 2 and 90% (40% Gr ≥3) at 6 mg/m 2 . Gr ≥3 zele-related AEs for 6 mg/m 2 (≥5% pts) included neutropenia (10%), neutrophil count decreased (7%), and anemia (7%). AEs related to pembro were reported in 80% (37% Gr ≥3) and 53% (13% Gr ≥3), respectively. Zele-related AEs of clinical interest (AECIs) for 6 mg/m 2 are summarized in the Table. Notably, no zele-related severe skin reactions of any Gr were reported at the 6 mg/m 2 dosage. Zele dose reductions and discontinuations due to zele-related AEs occurred in 20% and 3%, respectively, for 6 mg/m 2 . At Week 27, >50% of pts remained on tx. Conclusions: Zele at 5 mg/m 2 on D1/8/15 + pembro and 6 mg/m 2 on D1/8 + pembro on a 21-D cycle demonstrate encouraging response rates and safety profiles with the potential to differentiate from ADCs in previously untx pts. The 6 mg/m 2 D1/8 regimen demonstrated a more favorable benefit-risk profile to meet the need for safer and more tolerable treatments, with substantially reduced toxicity, better tolerability, improved potential for combinability, and enhanced convenience, leading to fewer discontinuations. Clinical trial information: NCT06225596 . Zele-related AECIs in pts with previously untx la/mUC treated with zele 6 mg/m 2 on D1/8 + pembro (N=30). AECI, n (%) Any Grade Grade ≥3 Peripheral neuropathy 11 (37) 1 (3) Skin reactions 5 (17) 0 Eye disorders 3 (10) 0 Hyperglycemia 0 0

OBJECTIVE:Evaluate the efficacy and safety of mirvetuximab soravtansine-gynx (MIRV) plus pembrolizumab in dose escalation and expansion cohorts of heavily pretreated patients with platinum-resistant ovarian cancer (PROC). METHODS:Participants with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer whose disease relapsed ≤6 months from last platinum-based treatment received MIRV (6 mg/kg adjusted ideal body weight) and pembrolizumab (200 mg) intravenously once every 3 weeks. Tumor FRα expression thresholds were ≥25 % (dose escalation cohort) and ≥50 % (dose expansion cohort) of cells with ≥2+ membrane staining intensity. The primary efficacy endpoint was objective response rate (ORR). Secondary endpoints included duration of response (DOR), progression-free survival (PFS), and safety. RESULTS:Fifty-six participants received the doublet. Median age was 62 years (range, 40-78). Twenty percent of participants had 3 prior lines of systemic treatment, 43 % had ≥4 prior lines, 43 % had prior bevacizumab exposure, and 41 % had prior PARP inhibitor exposure. Among 55 response-evaluable participants, ORR was 31 % (95 % CI, 19-45), median DOR was 8.0 months (95 % CI, 4.2-NR), and median PFS was 4.2 months (95 % CI, 2.8-5.6). Efficacy persisted in patients with multiple prior lines of treatment. Treatment-emergent adverse events were consistent with the profiles of each agent; the most common were diarrhea (all grades, 57 %; grade 3, 4 %), nausea (55 %; 5 %), and fatigue (50 %; 2 %). Treatment-emergent pneumonitis occurred in 25 % of participants, with grade ≥3 events occurring in 2 (4 %) participants. CONCLUSIONS:MIRV plus pembrolizumab demonstrated anti-cancer efficacy and a tolerable safety profile in heavily pretreated patients with PROC. However, the efficacy benefit may be mainly attributable to MIRV alone.

AimsMirvetuximab soravtansine is a first‐in‐class antibody–drug conjugate recently approved for the treatment of folate receptor‐α positive ovarian cancer. The aim of this study was to develop a population pharmacokinetic model to describe the concentration–time profiles of mirvetuximab soravtansine, the payload (DM4) and a metabolite (S‐methyl‐DM4).MethodsMirvetuximab soravtansine was administered intravenously from 0.15 to 7 mg/kg to 543 patients with predominantly platinum‐resistant ovarian cancer in 3 clinical studies, and the plasma drug concentrations were analysed using a nonlinear mixed‐effects modelling approach. Stepwise covariate modelling was performed to identify covariates.ResultsWe developed a semi‐mechanistic population pharmacokinetic model that included linear and nonlinear routes for the elimination of mirvetuximab soravtansine and a target compartment for the formation and disposition of the payload and metabolite in tumour cells. The clearance and volume of the central compartment were 0.0153 L/h and 2.63 L for mirvetuximab soravtansine, 8.83 L/h and 3.67 L for DM4, and 2.04 L/h and 6.3 L for S‐methyl‐DM4, respectively. Body weight, serum albumin and age were identified as statistically significant covariates. Exposures in patients with renal or hepatic impairment and who used concomitant cytochrome P450 (CYP) 3A4 inhibitors were estimated.ConclusionThere is no need for dose adjustment due to covariate effects for mirvetuximab soravtansine administered at the recommended dose of 6 mg/kg based on adjusted ideal body weight. Dose adjustment is not required for patients with mild or moderate renal impairment, mild hepatic impairment, or when concomitant weak and moderate CYP3A4 inhibitors are used.

OBJECTIVE:Mirvetuximab soravtansine-gynx (MIRV) is a novel antibody-drug conjugate targeting folate receptor alpha (FRα), which is overexpressed in epithelial ovarian cancer (EOC), with limited expression on normal tissues. This integrated safety summary sought to characterize the safety profile of MIRV monotherapy in participants with FRα-expressing recurrent EOC. METHODS:Safety data were retrospectively analyzed from 4 clinical studies (phase 1 trial [NCT01609556], phase 3 FORWARD I [NCT02631876], phase 2 SORAYA [NCT04296890], phase 3 MIRASOL [NCT04209855]) that evaluated participants with FRα-expressing recurrent EOC who received ≥1 dose of MIRV 6 mg/kg adjusted ideal body weight every 3 weeks. RESULTS:In this analysis of 682 participants, 94 % had platinum-resistant ovarian cancer (PROC). Blurred vision (43 %), nausea (41 %), diarrhea (39 %), and fatigue (35 %) were the most common treatment-emergent adverse events (TEAEs) and were primarily grade 1-2 in severity. Grade ≥ 3 TEAEs occurred in 48 % of participants, with the most common being keratopathy and blurred vision (5 % each). Most TEAEs were managed with supportive care and dose modifications, and only 12 % of participants experienced a TEAE leading to discontinuation (1 % due to ocular events). No corneal ulcerations or perforations have been reported. Median time to onset of blurred vision and keratopathy was 5.9 and 6.7 weeks, respectively. Most blurred vision events and keratopathy events resolved completely (71 % and 66 %, respectively) or partially (15 % and 14 %, respectively). CONCLUSIONS: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.

Objective The single-arm, phase II SORAYA trial ( NCT04296890 ) of mirvetuximab soravtansine-gynx in folate receptor alpha (FRα)–high platinum-resistant ovarian cancer (n=105 (efficacy-evaluable)) met its primary endpoint with an objective response rate of 32.4% (95% CI, 23.6 to 42.2). Here we report final SORAYA trial results for overall survival and post hoc objective response rates in subgroups by sequence and number of prior therapies. Methods Eligible patients had high-grade serous platinum-resistant ovarian cancer with high FRα expression and one to three prior therapies (prior bevacizumab required). Enrolled participants received 6 mg/kg mirvetuximab soravtansine-gynx adjusted ideal body weight intravenously once every 3 weeks until progressive disease, unacceptable toxicity, withdrawal of consent, or death. Final overall survival and post hoc objective response rates were assessed in efficacy-evaluable participants. The safety population included all patients who received ≥1 dose of mirvetuximab soravtansine-gynx. Results At data cut-off (December 22, 2022; n=105), final median overall survival was 15.0 months (95% CI, 11.5 to 18.7). Median overall survival in participants with one to two prior therapy lines was 18.7 months (95% CI, 13.8 to not estimable (NE)) and 11.6 months (95% CI, 7.1 to 16.7) with three prior therapy lines. Median overall survival was 15.0 months (95% CI, 11.5 to NE) in participants with prior poly (ADP-ribose) polymerase inhibitor (PARPi) treatment versus 14.0 months (95% CI, 7.1 to NE) in those without. Objective response rate (data cut-off: November 17, 2021) differed among participants who received mirvetuximab soravtansine-gynx as their first treatment in the platinum-resistant setting (34.8%; 95% CI, 23.5 to 47.6) versus a different first treatment (28.2%; 95% CI, 15.0 to 44.9) or had received prior bevacizumab in a platinum-sensitive (34.0%; 95% CI, 24.6 to 44.5) versus platinum-resistant setting (17.6%; 95% CI, 3.8 to 43.4). No new safety signals were observed. Conclusion These results support the clinically meaningful efficacy of mirvetuximab soravtansine-gynx in FRα-expressing platinum-resistant ovarian cancer, irrespective of prior treatment or sequence.

Objective. Evaluate the antitumor activity and safety profile of the triplet combination of mirvetuximab soravtansine (MIRV), carboplatin, and bevacizumab in recurrent, platinum -sensitive ovarian cancer. Methods. Participants with recurrent, platinum -sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer (1-2 prior lines of therapy) received MIRV (6 mg/kg adjusted ideal body weight), carboplatin (AUC5), and bevacizumab (15 mg/kg) once every 3 weeks. Carboplatin could be discontinued after 6 cycles per investigator discretion; continuation of MIRV+bevacizumab as maintenance therapy was permitted. Eligibility included folate receptor alpha (FR alpha) expression by immunohistochemistry (>= 50% of cells with >= 2+ intensity; PS2+ scoring); prior bevacizumab was allowed. Tumor response, duration of response (DOR), progression -free survival (PFS), and adverse events (AEs) were assessed. Results. Forty-one participants received triplet therapy, with a median of 6, 12, and 13 cycles of carboplatin, MIRV, and bevacizumab, respectively. The confirmed objective response rate was 83% (9 complete and 25 partial responses). The median DOR was 10.9 months; median PFS was 13.5 months. AEs (any grade) occurred as expected, based on each agent's safety profile; most common were diarrhea (83%), nausea (76%), fatigue (73%), thrombocytopenia (71%), and blurred vision (68%). Most cases were mild to moderate (grade <= 2), except for thrombocytopenia, for which most drug -related discontinuations occurred, and neutropenia. Conclusions. This triplet regimen (MIRV+carboplatin+bevacizumab) was highly active, with a tolerable AE profile in participants with recurrent, platinum -sensitive, FR alpha-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. (c) 2024 Published by Elsevier Inc.

Aims: This study aimed to investigate exposure-response (ER) relationships in efficacy and safety for mirvetuximab soravtansine (MIRV) which is a first-in-class antibody-drug conjugate approved for the treatment of folate receptor-alpha-positive alpha-positive platinum-resistant ovarian cancer. Methods: MIRV was characterized in 4 clinical studies. Exposure metrics for MIRV, its payload and a metabolite were derived from a population pharmacokinetic model. Efficacy was analysed in MIRV-treated patients (n n = 215) in a recent confirmatory, randomized, chemotherapy-controlled MIRASOL trial and safety was evaluated in patients pooled across all 4 clinical studies (n n = 757). Results: In the MIRASOL trial (NCT04209855), MIRV demonstrated significant benefit over chemotherapy in progression-free survival (PFS), objective response rate (ORR) and overall survival (OS). The most common adverse events (AEs) included ocular disorders, peripheral neuropathy and pneumonitis. For PFS, ORR and OS, the trough concentration of MIRV was the predictor consistently found in ER models for efficacy. In contrast, for ocular AEs (as well as the time to onset of ocular AEs) and peripheral neuropathy, the area under the concentration-time curve (AUC) of MIRV was identified as the exposure metric in ER models for safety. No exposure parameters were found to correlate with pneumonitis. Covariates in all models did not show clinically meaningful impact on efficacy or safety. Logistic regression models for ORR and ocular AEs based on AUC of MIRV were used to justify the clinical dose regimen approved for MIRV. Conclusion: 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.

PURPOSE:Evaluate the antitumor activity and safety profile of the combination of mirvetuximab soravtansine and bevacizumab in patients with platinum-resistant ovarian cancer. METHODS:Patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, whose most recent platinum-free interval was ≤6 months, were administered mirvetuximab soravtansine (6 mg/kg adjusted ideal body weight) and bevacizumab (15 mg/kg), intravenously, once every 3 weeks. Eligibility included FRα expression by immunohistochemistry (IHC; ≥25% of cells with ≥2+ intensity). Prior bevacizumab and/or PARP inhibitor (PARPi) treatment were permitted. The primary endpoint was confirmed objective response rate (ORR). Secondary endpoints included duration of response (DOR), progression-free survival (PFS), and safety. RESULTS:Ninety-four patients received combination treatment with mirvetuximab soravtansine and bevacizumab. Median age was 62 years (range, 39-81). Fifty-two percent had ≥3 prior therapies; 59% had prior bevacizumab; and 27% had prior PARPi. ORR was 44% (95% CI 33, 54) with 5 complete responses, median DOR 9.7 months (95% CI 6.9, 14.1), and median PFS 8.2 months (95% CI 6.8, 10.0). Treatment-related adverse events were consistent with the profiles of each agent, with the most common being blurred vision (all grades 57%; grade 3, 1%), diarrhea (54%; grade 3, 1%), and nausea (51%; grade 3, 1%). CONCLUSION:The mirvetuximab soravtansine plus bevacizumab doublet is an active and well-tolerated regimen in patients with FRα-expressing platinum-resistant ovarian cancer. Promising activity was observed for patients regardless of level of FRα expression or prior bevacizumab. These data underscore the potential for mirvetuximab soravtansine as the combination partner of choice for bevacizumab in this setting.

BACKGROUND:Mirvetuximab soravtansine-gynx (MIRV), a first-in-class antibody-drug conjugate targeting folate receptor α (FRα), is approved for the treatment of platinum-resistant ovarian cancer in the United States. METHODS:We conducted a phase 3, global, confirmatory, open-label, randomized, controlled trial to compare the efficacy and safety of MIRV with the investigator's choice of chemotherapy in the treatment of platinum-resistant, high-grade serous ovarian cancer. Participants who had previously received one to three lines of therapy and had high FRα tumor expression (≥75% of cells with ≥2+ staining intensity) were randomly assigned in a 1:1 ratio to receive MIRV (6 mg per kilogram of adjusted ideal body weight every 3 weeks) or chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary end point was investigator-assessed progression-free survival; key secondary analytic end points included objective response, overall survival, and participant-reported outcomes. RESULTS:A total of 453 participants underwent randomization; 227 were assigned to the MIRV group and 226 to the chemotherapy group. The median progression-free survival was 5.62 months (95% confidence interval [CI], 4.34 to 5.95) with MIRV and 3.98 months (95% CI, 2.86 to 4.47) with chemotherapy (P<0.001). An objective response occurred in 42.3% of the participants in the MIRV group and in 15.9% of those in the chemotherapy group (odds ratio, 3.81; 95% CI, 2.44 to 5.94; P<0.001). Overall survival was significantly longer with MIRV than with chemotherapy (median, 16.46 months vs. 12.75 months; hazard ratio for death, 0.67; 95% CI, 0.50 to 0.89; P = 0.005). During the treatment period, fewer adverse events of grade 3 or higher occurred with MIRV than with chemotherapy (41.7% vs. 54.1%), as did serious adverse events of any grade (23.9% vs. 32.9%) and events leading to discontinuation (9.2% vs. 15.9%). CONCLUSIONS:Among participants with platinum-resistant, FRα-positive ovarian cancer, treatment with MIRV showed a significant benefit over chemotherapy with respect to progression-free and overall survival and objective response. (Funded by ImmunoGen; MIRASOL ClinicalTrials.gov number, NCT04209855.).

Introduction/Background Mirvetuximab soravtansine (MIRV), an antibody-drug conjugate targeting folate receptor alpha (FRα), demonstrated an improvement in progression-free survival (PFS) and overall survival (OS) in patients (pts) with platinum-resistant ovarian cancer (PROC) compared to investigator choice chemotherapy (IC) (Moore K et al. ASCO 2023; LBA5507). Here we present efficacy data by prior PARPi (with nominal p-values). Methodology 453 PROC pts with high FRα expression with 1–3 priors were randomized 1:1 to MIRV or IC: paclitaxel, pegylated liposomal doxorubicin, or topotecan. Primary efficacy endpoint was PFS; key secondary endpoints: overall response rate (ORR), overall OS, and patient-reported outcomes (hierarchical order). Results 227 pts were randomized to the MIRV arm; 226 to the IC arm. Baseline characteristics were well balanced; 14% of pts had one, 39% two, and 47% three prior lines of therapy; 55% received prior PARPi. In pts with prior PARPi (n=251) PFS HR was 0.58 (95% confidence interval 0.43, 0.78, p-value=0.0002) and ORR 45% vs 17%, p-value <0.0001, favoring MIRV. In the PARPi-naïve subset (n=191), PFS HR was 0.74 (0.54, 1.03, p-value=0.0685) and ORR 40% vs 14%, p<0.0001. In pts with prior PARPi, MIRV had lower rates of grade 3+ treatment-emergent adverse events (TEAEs) (45% vs. 58%), serious TEAEs (21% vs. 35%), and discontinuations due to TEAEs (9% vs. 22%) compared with IC. Additional patient characteristics, safety, and OS data will be presented. Conclusion MIRV is the first treatment to demonstrate both an OS and a PFS benefit compared to IC in a phase III trial in PROC. In this subset analysis, the benefit extends to patients regardless of prior PARPi, with the greatest benefit in pts with prior PARPi exposure. These efficacy data, along with the well-characterized safety profile, position MIRV as a new standard of care for pts with FRα-positive PROC.

SORAYA is a global single-arm phase III study evaluating Mirvetuximab soravtansine (MIRV) in patients (pts) with folate receptor alpha (FRα) high platinum-resistant ovarian cancer (PROC). MIRV is an antibody-drug conjugate comprising an FRα-binding antibody, cleavable linker, and maytansinoid DM4, a potent tubulin-targeting agent. In this study, MIRV demonstrated activity in a broad population of PROC, regardless of the number of prior lines of therapy or prior PARPi (Matulonis, SGO 2022). Here we described details of the clinical response to MIRV throughout the treatment journey, which are important for clinical decision making. SORAYA enrolled PROC pts. with high FRα expression by immunohistochemistry (Roche FOLR1 Assay ≥75% of cells with PS2+ staining intensity) who had received 1–3 prior therapies, including required prior bevacizumab. Pts received intravenous MIRV at 6 mg/kg, adjusted ideal body weight, on day 1 of a 21-day cycle until disease progression or unacceptable toxicity. The primary endpoint was the confirmed objective response rate (ORR) per RECIST v1.1 by the investigator (INV), and the key secondary endpoint was the duration of response (DOR) safety and tolerability. A total of 106 pts. were enrolled; 51% had 3 prior lines, 48% had 1–2 prior lines of therapy, 37% of pts. had prior treatment in the PROC setting, and 100% of pts. received prior BEV, with 16% in the PROC setting. ORR by INV was 32.4% (95% CI: 23.6%–42.2%), including five complete responses, and DOR was 6.9 mos (95% CI: 5.6–9.7). The ORR in pts. who received prior treatment in the PROC setting was 28% (95% CI: 15.0%–44.9%) versus 35% (95% CI: 23.5%–47.6%) for pts. who received MIRV as the first treatment in the PROC setting. Pts who received BEV in the platinum-sensitive setting as maintenance or combination had an ORR of 34% (95% CI: 24.6%–44.5%) versus 18% (95% CI: 3.8%–43.4%) in pts. who received BEV in the PROC setting. The most common treatment-related adverse events (TRAE; all grade, grade 3–4) included blurred vision (41%, 6%), keratopathy (29%, 9%), and nausea (29%, 0%). TRAEs led to dose delays in 33%, dose reductions in 20%, and discontinuations in 9% of pts.; one patient discontinued treatment due to an ocular event. The tolerability profile of MIRV consists of low-grade, reversible ocular and GI events, managed with dose modifications and supportive care. Treatment options for pts. with PROC are limited. MIRV is the first biomarker-directed therapy demonstrating antitumor activity in pts. with FRα high PROC. These results support the clinically meaningful impact MIRV has for pts. with FRα high PROC, irrespective of the sequence of prior therapies. Trial Information: NCT04209855.

PURPOSE Single-agent chemotherapies have limited activity and considerable toxicity in patients with platinum-resistant epithelial ovarian cancer (PROC). Mirvetuximab soravtansine (MIRV) is an antibody-drug conjugate targeting folate receptor α (FRα). SORAYA is a single-arm, phase II study evaluating efficacy and safety of MIRV in patients with PROC. METHODS SORAYA enrolled FRα-high patients with PROC who had received one to three prior therapies, including required bevacizumab. The primary end point was confirmed objective response rate (ORR) by investigator; duration of response was the key secondary end point. RESULTS One hundred six patients were enrolled; 105 were evaluable for efficacy. All patients had received prior bevacizumab, 51% had three prior lines of therapy, and 48% received a prior poly ADP-ribose polymerase inhibitor. Median follow-up was 13.4 months. ORR was 32.4% (95% CI, 23.6 to 42.2), including five complete and 29 partial responses. The median duration of response was 6.9 months (95% CI, 5.6 to 9.7). In patients with one to two priors, the ORR by investigator was 35.3% (95% CI, 22.4 to 49.9) and in patients with three priors was 30.2% (95% CI, 18.3 to 44.3). The ORR by investigator was 38.0% (95% CI, 24.7 to 52.8) in patients with prior poly ADP-ribose polymerase inhibitor exposure and 27.5% (95% CI, 15.9 to 41.7) in those without. The most common treatment-related adverse events (all grade and grade 3-4) were blurred vision (41% and 6%), keratopathy (29% and 9%), and nausea (29% and 0%). Treatment-related adverse events led to dose delays, reductions, and discontinuations in 33%, 20%, and 9% of patients, respectively. CONCLUSION MIRV demonstrated consistent clinically meaningful antitumor activity and favorable tolerability and safety in patients with FRα-high PROC who had received up to three prior therapies, including bevacizumab, representing an important advance for this biomarker-selected population.

Introduction/Background Mirvetuximab soravtansine (MIRV), an antibody-drug conjugate targeting folate receptor alpha (FRα), demonstrated an improvement in progression-free survival (PFS) and overall survival (OS) in patients (pts) with platinum-resistant ovarian cancer (PROC) compared to investigator choice chemotherapy (IC) (Moore K et al. ASCO 2023; LBA5507). Here we present PFS and OS by prior lines of therapy (PLOT) in the intent-to-treat population. Methodology 453 PROC pts with high FRα expression (Roche FOLR1 Assay), 1–3 PLOT were randomized 1:1 to MIRV or IC: paclitaxel, pegylated liposomal doxorubicin, or topotecan. Primary endpoint was PFS; key secondary endpoints: objective response rate (ORR), OS, and patient-reported outcomes (PRO) (hierarchical order). Results 227 pts were randomized to the MIRV arm; 226 to the IC arm. Baseline characteristics were well balanced ; 14% of pts had one, 39% two, and 47% three PLOT. In pts with 1 or 2 PLOT (n=245), PFS hazard ratio (HR), 95% confidence interval was 0.61 (0.45, 0.81) ; and 3 PLOT (n=208), PFS HR was 0.71 (0.52, 0.98 ). In patients with 1 or 2 PLOT, OS HR was 0.66 (0.45, 0.98); and 3 PLOT OS HR was 0.65 (0.43, 0.96). Compared with IC, MIRV was associated with lower rates of grade 3+ treatment-emergent adverse events (TEAEs) (42% vs 54%), serious AEs (24% vs 33%), and discontinuations due to TEAEs (9% vs 16%). The key secondary PRO endpoint, EORTC QLQ-OV28 (abdominal/GI symptom scale), will be presented. Conclusion MIRV demonstrated a longer OS and PFS vs IC, regardless of the number of PLOT. MIRV is the first treatment to demonstrate both an OS and a PFS benefit in a phase III trial in PROC. These efficacy data, along with the well-characterized safety profile, position MIRV as a new standard of care for pts with FRα positive PROC.

Objectives Mirvetuximab soravtansine (MIRV) is a first-in-class ADC comprising a folate receptor α (FRα)-binding antibody, cleavable linker, and maytansinoid DM4 payload. Here, we present updated data from the single-arm study SORAYA on the clinical benefit and safety of MIRV in FRα-high platinum-resistant ovarian cancer (PROC). Methods Patients (N=106) received MIRV 6 mg/kg, adjusted ideal body weight, intravenously on Day 1 of a 3-week cycle. Patients must have received 1–3 prior therapies, including bevacizumab. FRα-high expression by immunohistochemistry (PS2+ ≥75%) was required. Responses were assessed by investigator using RECIST v1.1. Here we report tumor reduction and disease control rate (percent of patients with complete response, partial response, and stable disease of 12+ weeks). Results Characteristics of 106 patients enrolled are in table 1. Seventy-five patients (71%) experienced tumor reduction as their best response (figure 1) and the disease control rate (DCR) was 51.4% (95% CI 41.5, 61.3). The confirmed ORR was 32.4% (95% CI 23.6, 42.2), the median duration of response was 6.9 months (95% CI 5.6, 8.1), and the median progression-free survival was 4.3 months (95% CI 3.7, 5.1). Most frequent treatment-related adverse events (TRAE; all, grade 3+) related to study drug included blurred vision (41%, 6%), keratopathy (36%, 9%), nausea (29%, 0%), and dry eye (23%, 2%). Seven percent of patients discontinued treatment due to a TRAE. Conclusions MIRV demonstrated anti-tumor activity by tumor reduction and DCR in heavily pretreated patients with FRα-high PROC. These data support MIRV as a potential practice-changing, biomarker-driven therapy.

Abstract Background The National Comprehensive Cancer Network recommends that patients with hormone receptor-positive early breast cancer be considered for adjuvant endocrine therapy (ET) after primary treatment like surgical excision. Adjuvant chemotherapy (CT) use primarily depends on risk of recurrence. Biomarkers such as Ki-67 potentially have most value in patients with intermediate risk factors, such as involvement of 1–3 positive nodes. This study evaluated the use of Ki-67 testing and treatment patterns in patients with HR+, human epidermal growth factor receptor 2-negative early breast cancer. Methods This was an observational retrospective cohort study of patients with electronic medical records from January 2010 to August 2018 treated for HR+, HER2− early breast cancer at Sarah Cannon sites in the United States (US). Overall, 567 patients were randomly selected after using the eligibility criteria: female or male ≥18 years, without distant metastases, and with available physician and pathology reports. Multivariable logistic regression was used to investigate factors predicting Ki-67 testing and test results. Descriptive analyses were applied to treatment patterns. Results Multivariable logistic regression analyses found no clinical or pathological factors that predicted whether Ki-67 testing had been ordered by physicians. Of all tested patients (N = 130), having Grade-2 tumors (OR, 7.95 [95% CI: 2.05, 30.9]; p = 0.0027) or Grade-3 tumors (OR, 95.3 [95% CI, 11.9, 760.7]; p < 0.001) at initial diagnosis was a predictor of high Ki-67 expression (≥20%). Ki-67 expression was tested in 23.6% (61/258) of patients with 1–3 positive nodes; 54.1% of them (33/61) had high Ki-67 expression (≥20%). While having a higher grade tumor predicted high Ki-67 (≥20%), 28.6% of patients with Grade-1 tumors also had high Ki-67 expression. Neo-adjuvant therapy was received by 16.0% of patients (91/567), most of whom (66/91; 72.5%) received CT alone. Adjuvant therapy, either endocrine and/or chemotherapy, was received by 92.6% (525/567) of patients and by 67.0% (61/91) of those who received neo-adjuvant therapy. Most (428/525, 81.5%) received ET in the adjuvant treatment setting. Conclusions High grade tumors predicted high Ki-67 (≥20%) expression, but Ki-67 testing was not widely used in these US patients. Most HR+, HER2− early breast cancers were treated with adjuvant ET, with or without CT.

Introduction/Background Following implementation of targeted therapies to first-line treatment, repeated use of bevacizumab and/or PARPi is often not approved nor has been conclusively proven efficacious for all patients with recurrent ovarian cancer. Accordingly, new combination partners for platinum-based chemotherapy become crucial to improve outcome. For the antibody-drug conjugate, Mirvetuximab soravtansine (MIRV), containing a folate receptor alpha(FRα)-binding antibody, patients with high FRα expression according to PS2+ Scoring (cut-off: ≥75% of tumor cells with FRα membrane staining and ≥2+ intensity) had significant progression-free survival (PFS) improvements (hazard ratio: 0.55) compared to mono-chemotherapy (median PFS 5.6 vs 3.2 months,P=0.015) in the phase III FORWARD I trial. Preliminary data for combination of MIRV with carboplatin from the Phase Ib FORWARD II trial, an ORR of 71% in 17 patients with a median PFS of 15 months, and ORR of 80% in the FRα medium/high (>50% PS2+) subset of 10 patients was noted. MIRV is well-tolerated with a manageable safety profile. Methodology Eligible patients for this multicenter, randomized, two-arm, open-label, comparative phase II trial have recurrent, FRα high epithelial cancer of the ovary, fallopian tube or peritoneum and measurable disease. Patients are eligible for platinum-based chemotherapy, had at least one prior chemotherapy, but are not candidates to receive bevacizumab. Patients with wildtype BRCA1/2 mutation status and patients with a deleterious mutation and prior PARPi therapy can be included. Following pre-screening for high FRα expression, 136 patients are randomized (1:1) to a) experimental arm: Carboplatin + MIRV 6 mg/kg IV d1 (6 cycles q21d) followed by MIRV monotherapy until disease progression or b) control arm: Platinum-based chemotherapy (6 cycles) followed by PARPi or standard of care. The primary endpoint PFS will be assessed by modified RECIST 1.1. Key secondary endpoints include overall survival, ORR, and quality of life. NCT04274426 Results Enrolment started. Conclusion Trial in Progress.