Purpose:

MORAb-202, an antibody–drug conjugate containing farletuzumab and eribulin with a cathepsin-B cleavable linker, targets folate receptor α (FRα)–expressing tumor cells. The primary objective of this first-in-human study was to evaluate the safety and tolerability of MORAb-202 in patients with solid tumors.

Patients and Methods:

Patients ≥20 years with adequate organ function and FRα-positive solid tumors who failed to respond to standard therapy were eligible. Patients received MORAb-202 intravenously at doses of 0.3 to 1.2 mg/kg once every three weeks. Endpoints included dose-limiting toxicities, safety, tumor responses, pharmacokinetics, and pharmacodynamics. Trial registration number: NCT03386942 (ClinicalTrials.gov).

Results:

Between November 28, 2017 and June 4, 2019, 22 patients (median age, 58.0 years) with advanced solid tumors were enrolled. Treatment-emergent adverse events occurred in 21 (95%) patients, with leukopenia and neutropenia in 10 (45%) patients each. One patient (0.9 mg/kg cohort) experienced two grade 3 dose-limiting toxicities: serum alanine aminotransferase and γ-glutamyl transferase increases. Following review by an independent adjudication committee, grade 1/2 interstitial lung disease thought to be related to MORAb-202 was identified in five (23%) patients. Complete response, partial response, and stable disease were observed in one, nine, and eight patients, respectively. The normalized predose serum FRα tended to be positively correlated with the maximum tumor shrinkage (R2 = 0.2379; P = 0.0291).

Conclusions:

The MTD of MORAb-202 was not reached. MORAb-202 demonstrated promising antitumor activity in FRα-positive solid tumors and was generally well-tolerated at the tested doses. Further investigations are required to establish appropriate dosage and clinical utility of MORAb-202.

Translational Relevance

MORAb-202 is a novel antibody–drug conjugate that comprises farletuzumab (anti-folate receptor α antibody) linked to eribulin (microtubule inhibitor) as a payload. Eribulin displays unique activities in the tumor microenvironment, including vascular remodeling, reversal of epithelial–mesenchymal transition, and antimitotic activity. Antibody–drug conjugates with different payloads are expected to show different clinical efficacy and safety profiles. MORAb-202 displays a different mechanism of action compared with other antibody–drug conjugates. The novel cathepsin-B cleavable linker of MORAb-202 releases the active payload within target cells in lysosomal compartments but remains stable in serum. Thus, it may display fewer and less serious systemic toxic effects than other antibody–drug conjugates. This phase 1 study provides evidence of the acceptable safety, tolerability, and antitumor activity profiles of MORAb-202 in patients with advanced solid tumors who failed to respond to standard therapy, supporting further investigation of MORAb-202 in this setting.

Sufficient folate intake is required in rapidly proliferating cells to support single carbon metabolic reactions, and DNA synthesis, repair, and methylation (1, 2). Folate is transported by one of four glycopolypeptide folate receptors (FRα, FRβ, FRγ, and FRδ), with molecular weights ranging from 38 to 45 kDa (3, 4). These receptors are often expressed in subsets of malignant cells but are generally absent from normal tissue. They thus represent an attractive antitumor target (5, 6). FRα is a glycosylphosphatidylinositol-anchored membrane protein that is overexpressed in solid tumors, including ovarian, lung, and breast cancers (7).

Clinical trials are exploring the role of FR-targeted monoclonal antibodies and small-molecular drugs for imaging or treatment of FR-positive tumors (4). FRα-targeted therapies, including farletuzumab and MOv18-IgG1 (monoclonal antibodies), mirvetuximab soravtansine (an antibody–drug conjugate), and vintafolide (a small-molecule drug) have been studied for the treatment of lung and ovarian cancers (8).

Mirvetuximab soravtansine is an antibody–drug conjugate that, like MORAb-202, comprises an FRα-binding antibody, but is conjugated to the maytansinoid DM4. This complex showed preliminary antitumor activity in phase 1 trials (9, 10) and a completed phase 3 trial (11). Two additional phase 3 trials are ongoing (NCT04209855 and NCT04296890).

Farletuzumab, a humanized monoclonal antibody specific for FRα, is thought to induce immune-dependent cell death, although the exact underlying mechanism is unknown (12, 13). A phase 3 trial of farletuzumab along with standard chemotherapy for ovarian cancer after their first platinum-sensitive relapse has been conducted (14). Another phase 2 trial of farletuzumab along with standard chemotherapy for first relapsed, platinum-sensitive ovarian cancer with low CA-125 levels is ongoing (NCT02289950) (15). Phase 1 trials of farletuzumab in patients with epithelial ovarian cancer (16, 17) or solid tumors (18) have also been conducted. In the phase 3 trial, patients with ovarian cancer were randomized to farletuzumab 1.25 mg/kg, farletuzumab 2.5 mg/kg, or placebo, but neither farletuzumab dose met the primary endpoint [progression-free survival (PFS) vs. placebo (14)]. However, PFS and overall survival (OS) were greater in patients with higher farletuzumab exposure. This raises the possibility that strategies that increase exposure or facilitate targeted delivery of a highly potent antibody–drug conjugate may provide better antitumor effects.

Eribulin mesylate (eribulin), a synthetic analog of halichondrin B, inhibits microtubule dynamics and is approved for the treatment of metastatic breast cancer and soft tissue sarcoma, following primary therapies (19). Preclinical studies revealed that eribulin exerts antimitotic activity, promotes vascular remodeling, suppresses tumor cell migration and invasion, and reverses the epithelial-to-mesenchymal transition associated with malignancy (20–22). Eribulin was reported to improve OS in patients with advanced or metastatic breast cancer, especially in patients with HER2-negative disease (23).

MORAb-202 is an antibody–drug conjugate consisting of farletuzumab joined to eribulin by a cathepsin-B cleavable linker (24). The link is a reduced interchain disulphide that binds to maleimido-PEG2-valine-citrulline-p-aminobenzylcarbamyl-eribulin at an averaged drug-to-antibody ratio of 4.0 (24). MORAb-202 targets FRα-expressing tumor cells. Upon binding, free eribulin is released via lysosomal cathepsin-B–mediated cleavage. Spontaneous hydrolysis at the carbamate then releases the p-aminobenzyl group, enabling eribulin's antitumor activity (Supplementary Fig. S1) (ref. 24).

In this article, we introduce findings from the dose-escalation part of the first-in-human phase 1 study of MORAb-202 in patients with FRα-positive solid tumors (NCT03386942). The dose-expansion part (cohort expansion) of the study is ongoing.

Trial design and ethics

This study was an open-label, first-in-human, dose-escalation phase 1 trial done at a single site in Japan. The dose-escalation part was the first part of the study; a dose-expansion part is ongoing. The dose-escalation part aimed to identify dose-limiting toxicities and determine the MTD, using an accelerated modified toxicity probability interval (mTPI) design. The study protocol and all amendments were reviewed and approved by the institutional review board at the National Cancer Center Hospital. The study was conducted in compliance with the ethical principles of the Declaration of Helsinki and Good Clinical Practice. All participants provided written informed consent.

Patients

Patients ages ≥20 years with an immunohistologically confirmed FRα-positive solid tumor [(FRα-positive criteria: ≥5% cells with any intensity (+1, +2, +3)], who had failed to respond to standard therapy, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had adequate function of major organs were eligible. Patients with serous ovarian carcinoma, fallopian tube carcinoma, endometrial carcinoma, or non-small cell lung cancer (NSCLC) of the adenocarcinoma subtype could be enrolled without prior FRα-positive confirmation if their archived resected tumor specimens were available for retrospective immunohistochemical testing. The tumor FRα status was assessed by IHC [Folate Receptor alpha IHC assay Kit (mAb 26B3.F2); Biocare Medical] of archived tissue (n = 21) or core needle biopsy (n = 1).

Study conduct and administration of MORAb-202

MORAb-202 was administered intravenously every 3 weeks (on day 1), infused over at least 60 minutes in cycle 1 and over 30 minutes in subsequent cycles if no infusion-related reactions were observed. All subjects received premedication with oral acetaminophen (400 to 600 mg) 30 to 60 minutes before the first infusion. For patients without infusion-related reactions in cycle 1, premedication was not used in subsequent cycles. Secondary prophylaxis could be used at the investigator's discretion. On the basis of toxicity, subsequent cycles could either be postponed or dose reduced as deemed appropriate by the investigator. The dose of MORAb-202 was escalated from 0.3 to 1.2 mg/kg in four steps (0.3 → 0.45 → 0.68 → 0.90 → 1.2 mg/kg) according to the mTPI design (25) with cohort size modification (i.e., accelerated mTPI design; Supplementary Fig. S2). The mTPI is an adaptive method, which is simple, transparent, and inexpensive to implement as the 3 + 3 design. It uses a Bayesian statistical framework and a beta/binomial hierarchic model to calculate the posterior probabilities of three intervals that indicate the relative distance between the toxicity rate of each dose level to the target probability, pT (25). In this study, the following dose-escalation range rules were pre-defined. The dose-escalation range was 100% until the development of a treatment-related grade 2 toxicity in one subject, and once such a toxicity occurred, the range would be switched to 50%. Once a treatment-related grade 2 toxicity occurred in more than two subjects or a grade 3 toxicity occurred in more than one subject, the range was switched to 33%. The exception was the initial starting dose (0.3 mg/kg), which was fixed at three patients. After switching evaluation to three patients per cohort, the next dose level was determined according to the mTPI method.

The study doses were chosen on the basis of preclinical evaluations in which the minimum pharmacologically active dose and the highest nonseverely toxic dose were estimated to be 0.41 and 1.95 mg/kg, respectively, by extrapolating data from prior studies of mice (24) and monkeys (26), respectively, in accordance with the FDA Guidance for Industry (27).

Study objectives

The primary objective of the study was to evaluate the safety and tolerability profile of MORAb-202 in patients with solid tumors. Secondary objectives were to determine the MTD of MORAb-202; pharmacokinetics (PKs) of MORAb-202, total antibody, and free-eribulin; and treatment response in terms of proportions of subjects with an objective response, disease control, or clinical benefit. Exploratory objectives included identifying the pharmacodynamic markers of MORAb-202 treatment.

Safety was assessed by monitoring adverse events, infusion-related reactions, pneumonitis/interstitial lung disease (ILD), and serious adverse events. Treatment-emergent adverse events were defined as any adverse event occurring on or after the initial MORAb-202 dose, and any adverse event that increased in severity during the trial. Adverse events were assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Infusion-related reactions were defined as adverse events occurring within 1 day of MORAb-202 infusion. Such events included cytokine release syndrome (if confirmed by laboratory tests), flushing, fever, rigor/chill, sweating/diaphoresis, pruritus/itching, urticaria, bronchospasm/wheezing, or bronchial edema.

Dose-limiting toxicities were assessed during cycle 1 (days 1 to 21), and included any of the adverse events listed below, for which a causal relationship with MORAb-202 could not be ruled out. The dose-limiting toxicities were to be used to ascertain the MTD. Potential episodes of ILD that were retrospectively identified by CT imaging were evaluated by an external independent adjudication committee using ILD only as a unified term and graded by investigators according to the grade of pneumonitis in CTCAE version 4.03.

Blood samples were obtained for PK analyses and to measure the serum-free FRα concentrations.

The efficacy endpoints were the proportions of subjects with an objective response (complete response or partial response), disease control (complete response, partial response, or stable disease ≥5 weeks), and clinical benefit (complete response, partial response, or durable stable disease lasting ≥23 weeks), which were assessed by the investigator according to RECIST version 1.1.

The following adverse events were considered dose-limiting toxicities: febrile neutropenia; grade 4 neutropenia persisting for more than 7 days or neutropenia requiring administration of hematopoietic-stimulating agents; grade 4 thrombocytopenia or thrombocytopenia that requires platelet transfusion; grade 4 anemia or anemia requiring blood transfusion; grade 3 nonhematologic toxicities, except for abnormal clinical laboratory values with no clinical significance, adverse events that could be managed and controlled to grade ≤2 by maximal medical management, or grade ≥3 infusion-related reactions were not considered dose-limiting toxicities because they are stochastic and idiosyncratic events not related to dose; grade 4 non-hematologic toxicities; and adverse events in which the second treatment with MORAb-202 required postponement by more than 14 days from the scheduled day.

The M score was calculated as an index of FRα expression, as follows: M score = (3x + 2y + z)/6, where x = percentage of tumor stained at an intensity of 3+, y = percentage of tumor stained at an intensity of 2+, and z = percentage of tumor stained at an intensity 1+.

PK analyses and measurement of serum concentrations of circulating FRα

The PK and pharmacodynamic profiles of MORAb-202 were examined using serum samples obtained from the end of infusion on cycle 1 day 1 to predose on cycle 2 day 1.

Blood samples for PK analysis were obtained during cycles 1 and 2 at predose, end of infusion, 0.5, 1, 2, 4, and 24 hours after infusion, and post infusion on days 1, 4, 8, and 15. In cycles 3 to 6, blood samples were obtained at predose and after infusion on days 1 and 8.

Serum MORAb-202 concentrations were measured using a validated ligand-binding assay format designed to specifically quantify the toxin-conjugated antibody, where a drug-to-antibody ratio ≥1 represents the number of intact-linker–toxin conjugation sites on the antibody. Serum total antibody concentrations were measured using a validated ligand-binding assay format designed to detect farletuzumab, independent of the level of linker–toxin conjugation present (drug-to-antibody ratio ≥0). The calibration standards, quality controls, and serum samples of MORAb-202 and total antibody were diluted using the assay buffer (2% Tween-20 in Rexxip HN buffer). The interbatch accuracy and precision of MORAb-202 were ≤9.5% and ≤5.1%, respectively. The intrabatch accuracy and precision for MORAb-202 were ≤6.0% and ≤10.2%, respectively. The intrabatch accuracy and precision for the total antibody were ≤5.8% and ≤4.5%, respectively. The interbatch accuracy and precision for the total antibody were ≤6.9% and ≤15.3%, respectively. The assays were validated across the range of 0.4–80.0 μg/mL for MORAb-202 and 2.0–10.0 μg/mL for the total antibody. All samples met the acceptance criteria of within ±20%. Plasma released-eribulin concentrations were measured by LC/MS-MS, as follows. Eribulin along with an analog internal standard were extracted from human plasma by high-performance liquid chromatography using a Kinetex 2.6 μmol/L, C18, 50- × 3.0-mm column under gradient flow. The analyte and internal standard were detected using an AB Sciex API-6500 LC/MS-MS equipped with a positive electrospray ionization detection system with a calibration range of 0.200 to 100 ng/mL, using 200-μL aliquots of human samples. The interbatch accuracy and precision were ≤6.3% and ≤−3.0%, respectively. The intrabatch accuracy and precision ranged from −12.6% to 6.7%. All samples met the acceptance criteria of within ±15%. The retrospective analysis of FRα status, by immunohistochemical analysis of archived formalin-fixed, paraffin-embedded tumor tissue sections, was performed at a central laboratory after participant enrollment. PK parameters were calculated by noncompartmental methods using Phoenix WinNonlin Version 7.0 (Certara).

The serum concentrations of circulating FRα, lacking the FRα/MORAb-202 complex, were measured using an electrochemiluminescence immunoassay (ECLIA) based on the capture of biotin-labeled anti-FRα antibody [24H8.D3 for the circulating total concentration (free and FRα/MORAb-202 complex), and 26B3.F2, which shares a similar epitope to MORAb-202, for the circulating free FRα concentration] on a Meso Scale Discovery (MSD) Gold 96-well small-spot streptavidin-coated plate to capture FRα, followed by detection with ruthenium-labeled anti-FRα antibody (19D4.B7) and subsequent enhanced chemiluminescent detection on a plate reader (Quickplex SQ120). In detail, for the total FRα assay, the human serum levels of FRα are measured using an ECLIA in which biotin-labeled anti-FRα antibody (clone 24H.D3; Rockland Immunochemicals, Inc.) is used to capture FRα on a streptavidin-coated plate. The captured antibody is detected with a ruthenium-labeled anti-FRα antibody (Rockland, clone 19D4.B7) and electrochemiluminescence (ECL). A calibration curve based on the ECL signal responses for known FRα concentrations is generated using a four-parameter logistic curve fit and used to interpolate the concentrations of quality control (QC) and test samples. The QC standards are prepared using recombinant human FRα produced within the laboratory. The lower and upper limits of detection are 125 pg/mL and 125 ng/mL, respectively, in neat serum. The minimum required dilution is 1:50. The precision of QCs is within the acceptance criteria with pooled repeatability for all QC levels at a coefficient of variation (CV) of ≤4.7%, and intermediate precision for all QC levels at a CV of ≤13.3%. The accuracy for all QC levels has a bias of ≤11.4%. The FRα assay involves the same procedure, except for the use of a different biotin-labeled anti-FRα antibody clone (clone 26B3.F2; Rockland) to capture FRα. The lower and upper limits of quantification are 125 pg/mL and 125 ng/mL, respectively, in neat serum. The minimum required dilution is 1:50. The precision of QCs is within the acceptance criteria with pooled repeatability for all QC levels at a CV of ≤5.6%, and intermediate precision for all QC levels at a CV of ≤12.3%. The accuracy for all QC levels has a bias of ≤10.7%. All antibodies used in the assays were generated by Rockland Immunochemicals, Inc. and recombinant human FRα for the QC standards and calibrators was generated by Eisai Inc. for internal use; these antibodies and recombinant human FRα are not commercially available. The serum FRα concentration (in pg/mL) was normalized to the total primary length of the tumor measured at baseline (in mm) according to RECIST. Correlations were analyzed using Pearson's correlation coefficient.

Statistical analysis

The number of subjects in the dose-escalation part of the phase 1 study was to be approximately 25. Subjects were enrolled in a single subject cohort at first and seven cohorts of three subjects each were enrolled after increasing the cohort size from one to three due to toxicity. The number of cohorts was deemed appropriate to explore dose levels near the MTD and to evaluate safety profiles after each dose.

Safety and efficacy endpoints were analyzed in patients who received at least one dose of the study drug. Treatment-emergent adverse events were summarized by MedDRA system organ class and preferred term, and are reported as the number (percentage) of patients. Descriptive statistics were used to summarize serum and plasma concentration and PK parameters of MORAb-202. Tumor responses by RECIST version 1.1 were analyzed descriptively as the number (percentage) of patients. This study is registered with ClinicalTrials.gov (NCT03386942).

Patients

This study was conducted at a single center in Japan and the first enrolled patient received the first dose of MORAb-202 on November 28, 2017. The cutoff date for data analysis was November 22, 2019. Twenty-two patients were enrolled and received at least one dose of MORAb-202. The median age was 58 years [interquartile range (IQR), 46–64 years; Table 1; Supplementary Table S1]. Twenty patients were female. Cancer types included breast, endometrial, NSCLC, ovarian, and fallopian tube cancer; ovarian cancer was the most frequent, accounting for 12 (55%) of 22 patients. The Eastern Cooperative Oncology Group performance status at baseline was 0 in 15 (68%) of 22 patients. Three patients each received MORAb-202 at doses of 0.3, 0.45, and 1.2 mg/kg, six patients received 0.68 mg/kg, and seven patients received 0.9 mg/kg (Supplementary Fig. S2).

Table 1.

Patient characteristics.

MORAb-202 dose
0.3 mg/kg0.45 mg/kg0.68 mg/kg0.9 mg/kg1.2 mg/kgTotal
Characteristic(n = 3)(n = 3)(n = 6)(n = 7)(n = 3)(N = 22)
Age (y), median (IQR) 56 (40–72) 65 (60–73) 53 (42–64) 50 (45–60) 64 (49–72) 58 (46–64) 
Sex, n (%) 
 Male 2 (33) 2 (9) 
 Female 3 (100) 3 (100) 4 (67) 7 (100) 3 (100) 20 (91) 
ECOG PS, n (%) 
 0 2 (67) 2 (67) 4 (67) 6 (86) 1 (33) 15 (68) 
 1 1 (33) 1 (33) 2 (33) 1 (14) 2 (67) 7 (32) 
Measurable FRα, n (%) 3 (100) 3 (100) 5 (83) 7 (100) 3 (100) 21 (96) 
FRα (+) cell (%), mean (SD) 90 (8) 62 (24) 55 (34) 66 (23) 67 (13) 66 (26) 
FRα M score, mean (SD) 28 (3) 25 (14) 19 (16) 21 (9) 21 (6) 22 (11) 
MORAb-202 dose
0.3 mg/kg0.45 mg/kg0.68 mg/kg0.9 mg/kg1.2 mg/kgTotal
Characteristic(n = 3)(n = 3)(n = 6)(n = 7)(n = 3)(N = 22)
Age (y), median (IQR) 56 (40–72) 65 (60–73) 53 (42–64) 50 (45–60) 64 (49–72) 58 (46–64) 
Sex, n (%) 
 Male 2 (33) 2 (9) 
 Female 3 (100) 3 (100) 4 (67) 7 (100) 3 (100) 20 (91) 
ECOG PS, n (%) 
 0 2 (67) 2 (67) 4 (67) 6 (86) 1 (33) 15 (68) 
 1 1 (33) 1 (33) 2 (33) 1 (14) 2 (67) 7 (32) 
Measurable FRα, n (%) 3 (100) 3 (100) 5 (83) 7 (100) 3 (100) 21 (96) 
FRα (+) cell (%), mean (SD) 90 (8) 62 (24) 55 (34) 66 (23) 67 (13) 66 (26) 
FRα M score, mean (SD) 28 (3) 25 (14) 19 (16) 21 (9) 21 (6) 22 (11) 

Note: See Supplementary Table S1 for additional patient characteristics (weight, tumor type, and number of previous anticancer medications).

Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; FRα, folate receptor alpha; IQR, interquartile range; SD, standard deviation.

Safety

Treatment-emergent adverse events occurred in 21 (95%) of 22 patients, and are summarized in Table 2 overall and by grade in Supplementary Table S2. The most frequent events were leukopenia and neutropenia in 10 patients each (45%), alanine aminotransferase increased in seven (32%), and anemia and aspartate aminotransferase increased in six each (27%) of 22 patients. All hematological events (leukopenia, neutropenia, and anemia) were of grade 1 or 2; none were of grade 3 or above. There were six grade 3 treatment-emergent adverse events and one grade 4 treatment-emergent adverse event (amylase increased in the 0.68 mg/kg cohort). The most frequent grade 3 events were alanine aminotransferase increased and γ-glutamyl transferase increased (both in two patients). One patient in the 0.9 mg/kg cohort experienced grade 3 alanine aminotransferase increased and γ-glutamyl transferase increased, which were observed during cycle 1 and determined as dose-limiting toxicities. According to the prespecified criteria, the MTD of MORAb-202 was not reached at the tested doses. Four patients discontinued the study due to treatment-emergent adverse events: ileus in one, ILD in one (reported as grade 1 ILD by the investigator), and pneumonitis in two patients. The cases of ileus and ILD were considered serious; the latter was considered related to MORAb-202.

Table 2.

Summary of treatment-emergent adverse events.

Adverse eventn (%)Adverse eventn (%)
Any treatment-related adverse event 21 (95) Pneumonitis 3 (14) 
Leukopenia 10 (45) Constipation 2 (9) 
Neutropenia 10 (45) Cough 2 (9) 
ALT increased 7 (32) Eye disorder 2 (9) 
Anemia 6 (27) Hypoalbuminemia 2 (9) 
AST increased 6 (27) Ileus 2 (9) 
Nausea 5 (23) Lipase increased 2 (9) 
Pyrexia 4 (18) Lymphopenia 2 (9) 
Diarrhea 3 (14) Oropharyngeal pain 2 (9) 
Fatigue 3 (14) Peripheral sensory neuropathy 2 (9) 
GGT increased 3 (14) Vomiting 2 (9) 
Malaise 3 (14) Amylase increased 1 (5) 
Nasopharyngitis 3 (14)   
Adverse eventn (%)Adverse eventn (%)
Any treatment-related adverse event 21 (95) Pneumonitis 3 (14) 
Leukopenia 10 (45) Constipation 2 (9) 
Neutropenia 10 (45) Cough 2 (9) 
ALT increased 7 (32) Eye disorder 2 (9) 
Anemia 6 (27) Hypoalbuminemia 2 (9) 
AST increased 6 (27) Ileus 2 (9) 
Nausea 5 (23) Lipase increased 2 (9) 
Pyrexia 4 (18) Lymphopenia 2 (9) 
Diarrhea 3 (14) Oropharyngeal pain 2 (9) 
Fatigue 3 (14) Peripheral sensory neuropathy 2 (9) 
GGT increased 3 (14) Vomiting 2 (9) 
Malaise 3 (14) Amylase increased 1 (5) 
Nasopharyngitis 3 (14)   

Note: See Supplementary Table S2 for treatment-emergent adverse events according to the grade of the event. Percentages are based on the total number of subjects in the Safety Analysis Set. If a subject had two or more adverse events in the same preferred term with different Common Terminology Criteria for Adverse Events (CTCAE) grades, then the event with the highest grade was used for that subject. Adverse events of grade 3 or 4 are all listed. Grades 1 or 2 are listed by preferred term for events occurring in at least 5% of all subjects.

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, γ-glutamyl transferase.

Once evaluation of tolerability in the 1.2 mg/kg cohort was completed, some potential episodes of ILD were reported by the investigator. These events comprised grade 2 pneumonitis (two patients), grade 1 pneumonitis (one patient), grade 1 ILD (one patient), and grade 1 lung injury (one patient), as recorded using CTCAE terms. Therefore, a retrospective review was performed by the external independent adjudication committee, and five (23%) of 22 patients were considered to have experienced ILD related to MORAb-202; four of these cases corresponded to the grade 1/2 CTCAE terms pneumonitis, ILD, and lung injury recorded by the investigator. The other patient was recorded as having grade 1 pneumonia by the investigator. For one patient recorded as having grade 1 pneumonitis by the investigator, the independent adjudication committee adjudicated this as not ILD. No treatment-related deaths or deaths occurred within 30 days of the last dose of MORAb-202. One infusion-related reaction was observed at 1.2 mg/kg.

PK analysis

Preliminary PK data suggested that the maximum serum concentration of MORAb-202 was reached approximately 0.5 to 1.0 hours after the end of infusion. Half-life ranged from approximately 4 to 6 days, and steady-state was achieved immediately after the cycle 1 dose (Table 3). Serum MORAb-202 concentrations generally increased with increasing dose across the dose-range tested (0.3–1.2 mg/kg; Fig. 1A). The apparent volume of distribution at steady-state for MORAb-202 was low, and accumulation of MORAb-202 was not observed. The PK profile of the total antibody was similar to that of MORAb-202 and a small amount of eribulin was detected in plasma (Fig. 1B; Supplementary Table S3).

Table 3.

Summary of preliminary PK parameters of MORAb-202a.

MORAb-202 dose (mg/kg; N = 3 per dose)
Cycle 1Cycle 2
Parameter0.30.450.68e0.9f1.20.30.450.68e0.9e1.2
Cmaxb (μg/mL) 5.9 ± 0.8 10.8 ± 2.6 19.5 ± 4.8 25.2 ± 6.3 33.3 ± 11.0 6.1 ± 0.3 12.4 ± 2.3 19.2 ± 2.1 24.5 ± 4.4 31.6 ± 10.3 
AUCb,c (μg×h/mL) 610 ± 130 1,040 ± 421 1,970 ± 563 2,700 ± 515 3,020 ± 644 640 ± 118 1,340g ± 700 2,140 ± 497 3,090 ± 634 3,480 ± 733 
tmaxd (h) 0.5 (0.5–0.5) 1.0 (0.5–4.0) 1.0 (0.0–4.0) 0.5 (0.0–0.5) 1.0 (0.5–2.0) 0.5 (0.5–0.5) 0.5 (0.5–0.5) 0.5 (0.0–2.0) 0.75 (0.0–2.0) 1.0 (0.0–4.0) 
t1/2b (h) 92.5 ± 18.2 102 ± 36.4 116 ± 34.4 130 ± 17.4 116 ± 14.4 117 ± 21.3 120g ± 32.3 131 ± 22.6 153 ± 25.6 124 ± 21.2 
CLb (mL/h/kg) 0.5 ± 0.1 0.5 ± 0.2 0.4 ± 0.1 0.3 ± 0.1 0.4 ± 0.1 0.5 ± 0.1 0.4g ± 0.2 0.3 ± 0.1 0.3 ± 0.1 0.4 ± 0.1 
VSSb (mL/kg) 67.3 ± 7.7 62.7 ± 10.9 57.4 ± 13.7 61.3 ± 14.2 69.4 ± 20.2 76.5 ± 15.1 63.5g ± 19.5 61.1 ± 11.1 58.9 ± 11.2 63.6 ± 14.9 
MORAb-202 dose (mg/kg; N = 3 per dose)
Cycle 1Cycle 2
Parameter0.30.450.68e0.9f1.20.30.450.68e0.9e1.2
Cmaxb (μg/mL) 5.9 ± 0.8 10.8 ± 2.6 19.5 ± 4.8 25.2 ± 6.3 33.3 ± 11.0 6.1 ± 0.3 12.4 ± 2.3 19.2 ± 2.1 24.5 ± 4.4 31.6 ± 10.3 
AUCb,c (μg×h/mL) 610 ± 130 1,040 ± 421 1,970 ± 563 2,700 ± 515 3,020 ± 644 640 ± 118 1,340g ± 700 2,140 ± 497 3,090 ± 634 3,480 ± 733 
tmaxd (h) 0.5 (0.5–0.5) 1.0 (0.5–4.0) 1.0 (0.0–4.0) 0.5 (0.0–0.5) 1.0 (0.5–2.0) 0.5 (0.5–0.5) 0.5 (0.5–0.5) 0.5 (0.0–2.0) 0.75 (0.0–2.0) 1.0 (0.0–4.0) 
t1/2b (h) 92.5 ± 18.2 102 ± 36.4 116 ± 34.4 130 ± 17.4 116 ± 14.4 117 ± 21.3 120g ± 32.3 131 ± 22.6 153 ± 25.6 124 ± 21.2 
CLb (mL/h/kg) 0.5 ± 0.1 0.5 ± 0.2 0.4 ± 0.1 0.3 ± 0.1 0.4 ± 0.1 0.5 ± 0.1 0.4g ± 0.2 0.3 ± 0.1 0.3 ± 0.1 0.4 ± 0.1 
VSSb (mL/kg) 67.3 ± 7.7 62.7 ± 10.9 57.4 ± 13.7 61.3 ± 14.2 69.4 ± 20.2 76.5 ± 15.1 63.5g ± 19.5 61.1 ± 11.1 58.9 ± 11.2 63.6 ± 14.9 

Abbreviations: AUC, area under the concentration–time curve from 0 hours to infinity; CL, drug clearance; Cmax, maximum serum concentration; tmax, time at which Cmax was achieved; t1/2, terminal phase elimination half-life; VSS, apparent volume of distribution at steady-state.

aPharmcokinetic parameters were calculated by noncompartmental analysis method using preliminary concentration data and nominal time/dose (lower limit of quantification = 0.4 μg/mL).

bMean ± standard deviation.

cIn cycles 1 and 2.

dMedian (range) time elapsed from the end of infusion.

en = 6.

fn = 7.

gn = 2.

Figure 1.

Serum concentrations of MORAb-202, total antibody, and plasma concentrations of eribulin in cycles 1 and 2. A, Serum concentrations of MORAb-202 according to dose. B, Serum concentrations of MORAb-202, total antibody, and plasma concentrations of eribulin administered at doses of 1.2 mg/kg.

Figure 1.

Serum concentrations of MORAb-202, total antibody, and plasma concentrations of eribulin in cycles 1 and 2. A, Serum concentrations of MORAb-202 according to dose. B, Serum concentrations of MORAb-202, total antibody, and plasma concentrations of eribulin administered at doses of 1.2 mg/kg.

Close modal

Pharmacodynamic analysis

The PK/pharmacodynamic profiles of MORAb-202 were examined in serum samples obtained from the end of infusion on cycle 1 day 1 to predose on cycle 2 day 1. Serum concentrations of FRα at each time point were compared with concentration at cycle 1 day 1 predose for each patient to obtain relative value for serum FRα. Averaged relative serum FRα increased after administration of MORAb-202 in a dose-dependent manner (Fig. 2A). A spike increase in relative serum FRα was observed at 24 hours on cycle 1 day 2 (0.3–0.9 mg/kg cohorts) and cycle 1 day 4 (1.2 mg/kg cohort). Spikes returned to predose levels by cycle 2 day 1. Peaks of relative serum FRα level overlapped at the higher doses of 0.9 and 1.2 mg/kg at 24 hours on cycle 1 day 2. Similar levels of relative serum FRα after administration of 1.2 mg/kg of MORAb-202 were observed at cycle 1 days 2 and 4.

Figure 2.

Serum FRα and correlation with response. A, Relative serum FRα level from the end of infusion on cycle 1 day 1 to predose on cycle 2 day 1 according to MORAb-202 dose cohort. B, Correlation between normalized serum FRα concentrations and maximum tumor shrinkage. C, Normalized serum FRα concentrations according to best overall response. CR, complete response; FRα, folate receptor α; PD, progressive disease; PR, partial response; SD, stable disease.

Figure 2.

Serum FRα and correlation with response. A, Relative serum FRα level from the end of infusion on cycle 1 day 1 to predose on cycle 2 day 1 according to MORAb-202 dose cohort. B, Correlation between normalized serum FRα concentrations and maximum tumor shrinkage. C, Normalized serum FRα concentrations according to best overall response. CR, complete response; FRα, folate receptor α; PD, progressive disease; PR, partial response; SD, stable disease.

Close modal

We also investigated whether serum FRα is related to a change in tumor size, by normalizing the serum FRα concentration to RECIST length, which is used as a surrogate for tumor volume because a preclinical study demonstrated that the serum FRα level was proportionally increased by the volume of the tumor. The normalized predose serum FRα pre-dose on cycle 1 day 1 was positively correlated with the maximum tumor shrinkage (R2 = 0.2379; P = 0.0291; Fig. 2B). We also analyzed the distribution of normalized baseline serum FRα at study entry among subjects divided by their best overall response. Normalized serum FRα tended to be higher in patients with a confirmed complete response or partial response (Fig. 2C). Because only two patients were classified with progressive disease after exclusion of a third progressive disease patient (tumor shrinkage −6.9%) that was classified as a non specific target lesion, a comparison with this cohort was not meaningful (t test, P = 0.0511).

Antitumor activity

Among 22 patients, the best response was complete response in one patient (5%), partial response in nine patients (41%), and stable disease in eight patients (36%). The other four patients (18%) had progressive disease. A complete response was observed in one patient with ovarian cancer (0.9 mg/kg). Tumor responses were seen at doses ranging from the lowest (0.3 mg/kg) to the highest (1.2 mg/kg) doses (Supplementary Table S4), and in all four tumor types tested, including five patients with ovarian cancer (one receiving 0.68 mg/kg, two receiving 0.9 mg/kg, and two receiving 1.2 mg/kg), one with endometrial cancer (0.3 mg/kg), one with triple-negative breast cancer (0.68 mg/kg), and two with NSCLC (0.68 mg/kg; Fig. 3A). Figure 3B shows the swimmers plot for duration of treatment and response in individual patients. The median length of exposure to MORAb-202 was 84.0 days (IQR, 64–85 days). All patients were FRα-positive except for one patient whose tumor sample did not include sufficient tumor cells for IHC.

Figure 3.

A, Waterfall plot of percentage of change in lesion diameter, as determined by the investigators. B, Swimmers plot of duration of treatment, best overall response, and serum concentration of free FRα. In A, the values above the graph indicate the FRα expression level on tumor tissue. The values above/below each bar indicate the MORAb-202 dose. CR, complete response; FRα, folate receptor α; NSCLC, non–small cell lung cancer; PD, progressive disease; PR, partial response; SD, stable disease. The M score was calculated using the equation: M = (3x + 2y + z)/6, where x = % of tumor stained at intensity 3+, y = % of tumor stained at intensity 2+, z = % of tumor stained at intensity 1+. The FRα percentage is displayed as a white number in A, and is expressed as %/M score in B.

Figure 3.

A, Waterfall plot of percentage of change in lesion diameter, as determined by the investigators. B, Swimmers plot of duration of treatment, best overall response, and serum concentration of free FRα. In A, the values above the graph indicate the FRα expression level on tumor tissue. The values above/below each bar indicate the MORAb-202 dose. CR, complete response; FRα, folate receptor α; NSCLC, non–small cell lung cancer; PD, progressive disease; PR, partial response; SD, stable disease. The M score was calculated using the equation: M = (3x + 2y + z)/6, where x = % of tumor stained at intensity 3+, y = % of tumor stained at intensity 2+, z = % of tumor stained at intensity 1+. The FRα percentage is displayed as a white number in A, and is expressed as %/M score in B.

Close modal

This is the first report describing treatment with an FRα-targeted antibody–drug conjugate paired by a cathepsin-B cleavable linker to an eribulin payload in patients with FRα-positive solid tumors. MORAb-202 is an investigational agent in which farletuzumab is conjugated to eribulin at a drug-to-antibody ratio of 4.0 (24). Development of antibody–drug conjugates is a major research focus because these drugs can target a specific tumor cell antigen and potentially reduce systemic exposure and toxicity (28, 29).

This first-in-human study demonstrated that MORAb-202 is well-tolerated at doses of 0.3 to 1.2 mg/kg every 3 weeks. These doses yield eribulin at equivalent doses of 0.2 to 0.85 mg/m2, respectively, which are lower than the approved dose of eribulin mesylate: 1.4 mg/m2 (equivalent to 1.23 mg/m2 eribulin) on days 1 and 8 of a 21-day cycle. Grade 3 treatment-emergent adverse events (alanine aminotransferase increased and γ-glutamyl transferase increased) occurred in two patients. No cases of grade 3 bone-marrow suppression occurred, which indicates a mild safety profile. Another FRα-targeted antibody–drug conjugate, mirvetuximab soravtansine, caused ocular toxicity (blurred vision: 42%, keratopathy: 33%, dry eye: 26%) in phase 3 (11) and phase 1 trials (9, 10). The eye disorders in our study were of grade 1 and infrequent [two (9%) of 22 patients]. This difference might be due to the different payloads transported by these conjugates.

In the present study, we did not reach the MTD of MORAb-202. As indicated in Supplementary Fig. S2, the highest non-severely toxic dose of MORAb-202 was estimated as 1.95 mg/kg (26) and MORAb-202 at doses of 0.41 mg/kg or higher exhibited antitumor activity in preclinical animal models (24). In addition, multiple patients experienced CR or PR at doses of 0.68 mg/kg or higher (Fig. 3A; Supplementary Table S4). Considering that this is the first-in-human study and the toxicity profile of MORAb-202 in humans was unknown, we prespecified a lower maximum dose of 1.2 mg/kg in this dose-escalation part and elected to expand the 0.9 mg/kg and higher-dose cohorts in the expansion part to mitigate the risk of severe ILD and to further assess the balance between the antitumor activity of MORAb-202 and the risk of ILD. In hindsight, it is possible that the MTD may have been reached if the study included additional groups treated at dose levels above 1.2 mg/kg. Ongoing and future studies may evaluate the pharmacology, safety, and efficacy of higher doses of MORAb-202.

All subjects were premedicated with acetaminophen before the first infusion of MORAb-202. Except for one patient who had a grade 1 infusion-related reaction at 1.2 mg/kg, no reactions were observed at the first infusion, so acetaminophen prophylaxis was not repeated in subsequent infusions. Notably, no infusion-related reactions were observed in subsequent infusions. Although ILD was observed in five (23%) of 22 patients, none were severe [grade 1 (three patients) and grade 2 (two patients) by investigator judgment]. One of the patients with grade 2 ILDs recovered by prednisolone treatment and the other improved without any treatment. One of the three patients with grade 1 ILDs recovered without medication and the other two patients had not yet recovered at the 3-week follow-up after the last dose. Most events were detected by a retrospective review approximately 12 weeks after the first infusion of MORAb-202. After recognizing these adverse events, we amended the study to implement ILD management guidelines and convened an external independent adjudication committee to monitor possible cases of ILD. Although data on the treatment of ILD associated with MORAb-202 are limited, interruption of MORAb-202 and administration of glucocorticoids may reduce the severity of ILD. Prior clinical studies have also documented ILD (0.36%) and pneumonitis (1.56%–3.23%) in patients treated with farletuzumab (30, 31) as well as drug-related lung injury in patients treated with eribulin (2.8%) (32). Thus far, the potential mechanism underlying the development of ILD in patients treated with MORAb-202 has not yet been clarified, and further clinical and preclinical studies are needed.

The PK profile of total antibody was similar to that of MORAb-202 and the plasma concentrations of eribulin were low, suggesting that little eribulin is released into plasma. We conclude that MORAb-202 demonstrates favorable PK with good stability in blood. Furthermore, the eribulin component is not released prematurely into blood, facilitating its release within the target FRα-positive tumor.

In this dose-escalation part of the phase 1 study, there were one complete response and nine partial responses to MORAb-202. Among the enrolled patients, the FRα expression level and intensity were lower in patients with triple-negative breast cancer. MORAb-202 exhibited antitumor activity via a bystander killing effect in a patient-derived xenograft model with low FRα expression, which is likely to result from enhanced membrane permeability of the eribulin payload (26). Furthermore, MORAb-202 achieved a greater bystander effect than farletuzumab conjugated to the same payload of mirvetuximab soravtansine in vitro (33). This indicates that MORAb-202 provides a greater bystander killing effect by diffusing into nearby tumor cells around the target tumor, even if the target tumor expresses a low level of FRα. The preliminary results in this study, together with preclinical data, suggest that MORAb-202 may be beneficial for the treatment of tumors with low FRα expression level and intensity, and could be used to target a broader population, not restricted to tumors with high FRα expression, because mirvetuximab soravtansine is being evaluated in a phase 3 trial targeting platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer (34).

Serum FRα is considered a biomarker for certain epithelial tumors such as ovarian cancer (35). Higher serum concentrations of FRα are indicative of a tumor's FRα expression status, and are correlated with clinical stage and poor prognosis. The serum concentrations of FRα on days 1 to 4 of cycle 1 suggest the possibility that MORAb-202 was engaged in FRα-positive tumors rather than artificially binding to non-cancerous FRα-positive tissue. A similar spike was observed in males with NSCLC, which may suggest the possibility of tumor antigen-specific binding. To address this possibility, it will be necessary to conduct additional analyses of each patient in all cycles. Preclinical data actually support specific binding of MORAb-202 to FRα-positive tumors, even if FRα expression is relatively low (Furuuchi K. et al., personal communication). An increase in the serum FRα concentration was observed in mice bearing human-FRα-positive xenografts treated with MORAb-202 (Furuuchi K. et al., personal communications). It will thus be intriguing to see how the spike in the relative serum FRα levels varied with ongoing treatment cycles. It is important to determine the significance of serum FRα concentrations. In preclinical studies, the serum FRα concentration increased in proportion to the tumor volume. Once the concentration was normalized by tumor volume, the relative baseline values were similar among patients, which allowed us to analyze the relationship between the normalized serum FRα concentration and dose and time dependency, as well as tumor shrinkage. Therefore, this approach permitted us to investigate the potential clinical relevance of the normalized serum FRα concentration. Interestingly, normalized serum FRα was correlated with the maximum tumor shrinkage and tended to increase at the time of the best overall response. This response occurred even though the total number remained limited and heterogeneous tumor types with various dosages of MORAb-202 were analyzed. Nevertheless, the available data suggest the normalized serum FRα concentration might be a clinically relevant biomarker for monitoring the prognosis of MORAb-202 treatment, and further investigation of this hypothesis may be warranted.

Results from this phase 1 dose-escalation part suggest that MORAb-202 is well tolerated, with a mild and manageable toxicity profile, including ILD. Importantly, MORAb-202 showed antitumor activities in various tumors (ovarian cancer, endometrial cancer, triple-negative breast cancer, and NSCLC) that had relapsed after failure to respond to standard therapy and displayed heterogeneous characteristics. Even though our findings were observed in a small heterogeneous population, they support future clinical studies of MORAb-202 as a potential new treatment modality for FRα-positive tumors. For further assessment of antitumor activity and safety, including ILD, in each tumor type, the expansion part of this phase 1 study and an additional study (36) are ongoing.

T. Shimizu reports grants from Eisai during the conduct of the study, as well as grants from Novartis, Pfizer, Eli Lilly, LOXO Oncology, Bristol Myers Squibb, AstraZeneca, Incyte, Symbio Pharmaceuticals, Chordia Therapeutics, 3D-Medicine, Five Prime, PharmaMar, and Astellas; grants and personal fees from AbbVie, Daiichi-Sankyo, and Takeda Oncology; and personal fees from Taiho and MSD outside the submitted work. Y. Fujiwara reports grants and personal fees from Astra Zeneca, Bristol Myers Squibb, Chugai Pharma, Daiichi Sankyo, MSD, and Novartis; grants from AbbVie, Eisai, Eli Lilly, Incyte, and Merck Serono; and personal fees from Ono Pharmaceutical outside the submitted work. K. Yonemori reports personal fees from Eisai, Pfizer, AstraZeneca, Ono Pharmaceutical, Novartis, Chugai Pharmaceutical and Takeda Pharmaceutical, outside the submitted work. T. Koyama reports other support from Sysmex and Chugai and grants from Pact Pharma outside the submitted work. A. Shimomura reports grants and personal fees from Chugai Pharmaceutical, AstraZeneca, and Daiichi Sankyo; personal fees from Pfizer, Eli-Lilly, and Novartis; and grants from Mochida Pharmaceutical and Taiho Pharmaceutical outside the submitted work. H. Ikezawa reports other support from Eisai Co., Ltd. during the conduct of the study. K. Furuuchi reports personal fees from Eisai Inc. during the conduct of the study; in addition, K. Furuuchi has a patent for WO2017151979A1 issued. N. Yamamoto reports other support from ONO, Janssen Pharma, MSD, Boehringer Ingelheim, Chugai, Otsuka, Eisai, Taiho, BMS, Novartis, Eli Lilly, AbbVie, Daiichi-Sankyo, Bayer, Takeda, MERCK, GSK, Sumitomo Dainippon, and Chiome Bioscience outside the submitted work. No disclosures were reported by the other authors.

T. Shimizu: Resources, data curation, supervision, investigation, writing–original draft, writing–review and editing. Y. Fujiwara: Conceptualization, resources, data curation, investigation, writing–review and editing. K. Yonemori: Resources, data curation, investigation, writing–review and editing. T. Koyama: Resources, data curation, investigation, writing–review and editing. J. Sato: Resources, data curation, investigation, writing–review and editing. K. Tamura: Resources, data curation, investigation, writing–review and editing. A. Shimomura: Resources, data curation, investigation, writing–review and editing. H. Ikezawa: Conceptualization, resources, software, formal analysis, visualization, methodology, writing–review and editing. M. Nomoto: Resources, formal analysis, visualization, writing–original draft, writing–review and editing. K. Furuuchi: Resources, validation, visualization, writing–original draft, writing–review and editing. R. Nakajima: Conceptualization, funding acquisition, validation, writing–original draft, project administration, writing–review and editing. T. Miura: Data curation, validation, visualization, project administration, writing–review and editing. N. Yamamoto: Conceptualization, resources, data curation, supervision, investigation, writing–review and editing.

This study was sponsored by Eisai Co., Ltd. We thank the patients who participated in this study, as well as their families and caregivers. We thank Noriyuki Katsumata of the Department of Medical Oncology at Nippon Medical School Musashikosugi Hospital, Kanagawa, Japan, who served as the safety advisor for this study. We thank Akira Tomonari as the medical expert for this study, and Toshimitsu Uenaka and Seiichi Hayato as the advisors for biomarker analysis, all of whom are employed by Eisai. Medical writing support was provided by Aafrin Khan (Enago Life Sciences, India) and Nicholas D. Smith (EMC K.K.), and was funded by Eisai, Tokyo, Japan.

Eisai was involved in all aspects of study design, data collection, data analysis, data interpretation, assisted in writing the report, and approved the final version of the manuscript for publication in conjunction with the authors. Hiroki Ikezawa, Maiko Nomoto, Keiji Furuuchi, Ryo Nakajima, and Takuma Miura had access to the raw data. The corresponding author had full access to all data in the study and had final responsibility for submitting the manuscript for publication.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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