Lorvotuzumab Mertansine Research Articles

Emerging Immune Targets for Treatment of Multiple Myeloma

Introduction:Multiple myeloma (MM) is the 14th leading cause of cancer deaths in the USA. According to NIH cancer statistics, there will be estimated 30,280 new cases and 12,590 deaths due to MM in 2017. Immunotherapy appears to be an appealing treatment modality for MM. Various immunotherapeutic approaches are being used and our aim is to summarize current knowledge on efficacy of non-FDA approved monoclonal antibodies (mAbs), chimeric antigen receptor modified (CAR-T) cells and their targets.Methods:For CAR-T cells literature search was performed on 7/16/2017 in following databases: PubMed, Cochrane, EMBASE, Web of Science and Clinicaltrilas.gov. Only English language studies were included and no publication date limit was applied. For mAbs, phase I/II trials that were complete or recruiting participants were retrieved from clinicaltrials.gov on 7/19/2017. Trials on elotuzumab and daratumumab that have already proven efficacy were not included.Results:Literature search identified a total of 287 articles on CAR-T cells. After detailed scrutiny, 6 studies were included. Citation analysis retrieved one additional study. 7 studies included 86 relapsed and refractory MM (RRMM) patients. Targeted antigens included B-cell maturation antigen (BCMA) (n=4 studies), CD138 (n=1), CD19(n=1) and kappa light chain (n=1). There was significant variation in CAR T cell dose ranging from 1 x 10⁷ to 5 x 10⁸ per patient. Most patients were heavily pretreated with ≥ 6 median prior lines of therapy. Only one study additionally incorporated ASCT. No objective response (OR) was achieved with CD138 and kappa light chain directed CAR T cell therapy. For BCMA and CD19 directed CAR T cell therapy, there was significant variation in efficacy outcomes reported with PR ranging from 2 weeks to 3.2 months (m), VGPR 2m to 5m and sCR 2m to 7+m. Highest incidence of cytokine release syndrome (CRS) of all grades was reported with BCMA directed CAR T cell therapy, ranging from 58-83%. One case of posterior reversible encephalopathy syndrome was reported with BCMA targeted CAR T cell therapy.mAb targets included ICAM-I (BI-505), IL-6 (siltuximab), VEGF (bevacizumab), GRP78 (PAT-SMX), CD40 (dacetuzumab, lucatumumab), CD138 (indatuximab), PD-1 (pembrolizumab, nivolumab, pidilizumab), CD20 (rituximab), CD38 (isatuximab), CD56 (lorvotuzumab), IGF-1R (AVE1642, figitumumab), VEGF (bevacizumab), BAFF (atacicept, tabalumumab) and CD74 (milatuzumab). No objective response (≥PR) was observed with monotherapy with BI-505, siltuximab, bevacizumab, PAT-SMX, AVE-1642, figitumumab, atacicept, milatuzumab, dacetuzumab and nivolumab. Isatuximab (anti-CD38) was the only mAb with promising results (OR 24%) as monotherapy in patients with 6 prior lines of therapy. Most trials employed RRMM patients. Siltuximab in combination with VMP (velcade, melphalan and prednisone) was evaluated in frontline setting without significant improvement reported (CR of 22% vs 27% with VMP alone and PFS of 17 months in both arms). Antibodies tested as conjugates include indatuximab, ravtansine (anti CD138) and lorvotuzumab mertansine (anti CD56). Their results were encouraging when used in combination with Rd (lenalidomide and dexamethasone), OR of 78% with indatuximab +Rd and 56.4% with lorvotuzumab +Rd. MAbs that've been tested in combination therapy include siltuximab (S+Vd, OR 66%), dacetuzumab (D+Rd, OR 39%), indatuximab (I+Rd, OR 78%), isatuximab (I+Rd, OR 64.5%), lorvotuzumab (L+Rd, OR 56.4%) and pembrolizumab (P+Pd, OR 50%).Conclusion:Immunotherapy with mAb and CAR-T therapy seems to offer very promising results. Short term and log term toxicity with mAb and cellular therapy demands thorough understanding of mechanism, biology behind the “ on target” and “off target” effects, side effect profile and their prevention. Further trials are warranted to determine best CAR-T cell construct and design for treating MM. Outcomes with many single agent mAb therapy were not encouraging and provide a rationale that future trials with mAbs should be done as multi-agent therapies. Promising results with isatuximab warrants further trials. Antibody-drug conjugate treatment is worth further evaluation both as single agent and in combination with standard anti-MM agents. Individualized treatment approach based on surface CD marker expression need to be developed and may produce better outcomes. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

NCAM1/FGF module serves as a putative pleuropulmonary blastoma therapeutic target

Pleuropulmonary blastoma (PPB) is a rare pediatric lung neoplasm that recapitulates developmental pathways of early embryonic lungs. As lung development proceeds with highly regulated mesenchymal-epithelial interactions, a DICER1 mutation in PPB generates a faulty lung differentiation program with resultant biphasic tumors composed of a primitive epithelial and mesenchymal stroma with early progenitor blastomatous cells. Deciphering of PPB progression has been hampered by the difficulty of culturing PPB cells, and specifically progenitor blastomatous cells. Here, we show that in contrast with in-vitro culture, establishment of PPB patient-derived xenograft (PDX) in NOD-SCID mice selects for highly proliferating progenitor blastoma overexpressing critical regulators of lung development and multiple imprinted genes. These stem-like tumors were sequentially interrogated by gene profiling to show a FGF module that is activated alongside Neural cell adhesion molecule 1 (NCAM1). Targeting the progenitor blastoma and these transitions with an anti-NCAM1 immunoconjugate (Lorvotuzumab mertansine) inhibited tumor growth and progression providing new paradigms for PPB therapeutics. Altogether, our novel in-vivo PPB xenograft model allowed us to enrich for highly proliferating stem-like cells and to identify FGFR and NCAM1 as two key players that can serve as therapeutic targets in this poorly understood and aggressive disease.

Antibodies in Development for Multiple Myeloma: A Systematic Review

IntroductionImmunotherapy using monoclonal antibodies (mAbs) have been gaining significance in the treatment of multiple myeloma (MM). These include naked antibodies, checkpoint inhibitors (CPIs), novel bispecific mAbs targeting two epitopes and antibody-drug conjugates (ADCs) having a mAb conjugated to a cytotoxic drug. This review aims to summarize phase I and I/II clinical trials using mABs for the treatment of MM.MethodsA comprehensive literature search using data from PubMed, Embase, AdisInsight and Clinicaltrials.gov was performed for identification of early phase (I and I/II) trials of mAbs in MM treatment (January 2008 to December 2017). Studies involving mAbs including targeting antibodies, ADCs, CPIs and bispecific mAbs were included, without considering the geo-location, age, sex or specific eligibility criteria. Drugs already approved by FDA were excluded.ResultsTotal of 2537 phase I and phase I/II studies were identified. After screening by two reviewers and categorization by their mechanism of action, 74 clinical trials (CTs) that involved mAbs as monotherapy or in combination with other chemotherapeutic drugs for the treatment of newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM). 41 CTs are active, completed or discontinued (Table 1) and 33 CTs are recruiting, approved for recruitment or planned. Most explored mechanism of action in these trials was mAb therapy directed against CD38, IL-6, huCD40, PD-L1 and PD-1.Isatuximab (Anti-CD38) has shown objective response rate (ORR) of >50% in combination with lenalidomide (R) or pomalidomide (P) plus dexamethasone (d) in ongoing phase I trials NCT01749969 (n=57) and NCT02283775 (n=89) respectively. According to Vij et al. (2016) and Mikhael et al. (2018), 54% ORR (n=31) and 62% ORR (n=28) was shown by combination of isatuximab with Rd and Pd in 57 and 45 evaluable RRMM patients, respectively. In Vij et al. (2016) study, stringent complete response (sCR) in 2 (3%) patients, very good partial response (VGPR) in 13 (23%) and partial response (PR) in 16 (28%) patients was observed. In Mikhael et al. (2018) study, sCR in 1 (2%) patient, CR in 1 (2%), VGPR in 10 (21%) and PR in 16 (34%) patients was observed. In comparison, Martin et al. (2014) mentioned ORR of only 24% with isatuximab monotherapy in 34 RRMM patients. Grade (G) ≥3 pneumonia (n=4) was the most common high-grade adverse events (AEs) being reported (Table 2).Siltuximab (Anti-IL-6) has shown clinical efficacy in combination with bortezomib (V) + d and RVd in phase I and I/II CTs. Shah et al. (2016) and Suzuki et al. (2015) found ORR to be 90.9% and 67% in 11 (NDMM) and 9 (RRMM) patients when siltuximab was given combined with RVd and Vd, respectively. Clinical benefit response (CBR) i.e. ≥ minimal response (MR) was 100% with siltuximab + RVd in NDMM patients. In comparison, siltuximab monotherapy in 13 RRMM patients yielded an ORR of 15% (2 CR) as reported by Kurzrock et al. (2012). G≥3 neutropenia (n=9), G≥3 thrombocytopenia (n=6) and G≥3 lymphopenia (n=8) were most common reported high-grade AEs.Checkpoint inhibitors including pembrolizumab (anti-PD-1) and pidilizumab (anti-PD-L1) are being investigated in RRMM treatment. According to Otero et al. (2017) and Ribrag et al. (2017), 50% ORR was obtained with pembrolizumab combined with Rd compared to 0% with monotherapy, respectively. However, combination therapy was associated with G≥3 neutropenia (n=17), thrombocytopenia (n=9) and anemia (n=6) while no high-grade AEs were observed with monotherapy.Antibody-Drug conjugates including lorvotuzumab mertansine and indatuximab ravtansine have been investigated in CTs for MM treatment. Lorvotuzumab mertansine has shown clinical efficacy in combination with Rd in a phase I trial (NCT00991562). Berdeja et al. (2012) reported an ORR of 59% (1 sCR, 1 CR, 8 VGPR, 9 PR) in 32 RRMM patients. In a phase I/II trial (NCT01638936) of indatuximab ravtansine combined with either Rd or Pd, Kelly et al. (2016) showed ORR of 77% with Rd (n=43) including at least 1 CR and 4 VGPR and 79% with Pd (n=14) including 4 VGPR in total 57 RRMM patients.ConclusionCombination regimens including monoclonal antibodies, CPIs and ADCs have shown clinically significant response in RRMM and NDMM patients. The mAbs caused hematological and nonhematological AEs like cytopenias and infections which needs to be monitored closely. DisclosuresNo relevant conflicts of interest to declare.

A Phase I Study to Assess the Safety and Pharmacokinetics of Single-agent Lorvotuzumab Mertansine (IMGN901) in Patients with Relapsed and/or Refractory CD–56-positive Multiple Myeloma

BackgroundDespite therapeutic advancements that have significantly improved outcomes in multiple myeloma (MM), it remains an incurable disease. Patients with relapsed and/or refractory MM have an aggressive disease course, with inferior outcomes, necessitating the need for agents with novel therapeutic mechanisms. We present the results of a completed phase I trial of single-agent lorvotuzumab mertansine, a unique antibody-drug conjugate targeting CD56, which is frequently expressed in MM. Patients and MethodsThirty-seven patients with relapsed MM were enrolled in a dose-escalation phase I clinical trial to determine the maximum tolerated dose of lorvotuzumab mertansine (112 mg/m2), followed by an expansion phase at the maximum tolerated dose. ResultsDespite a high proportion of patients with relapsed and/or refractory MM (56.8%), stable disease or better was noted in 42.9% of patients, and these patients had a long duration of response (median, 15.5 months). The adverse event profile was favorable, with a low incidence of grade 3/4 adverse events and no infusion-related reactions. No humoral responses were detected against the study drug. ConclusionThis completed phase I trial of single-agent lorvotuzumab mertansine provides ample evidence of safety and signals of clinical activity for this agent, warranting its further clinical development as part of combination regimens for the management of MM.

Advances in antibody therapeutics targeting small-cell lung cancer.

The proportion of small-cell lung cancer (SCLC) among all lung cancers decreased from 17.26% in 1986 to 12.95% in 2002. Chemotherapy is the key mode of treatment. However, novel therapeutic strategies and drugs are imperative, as the prognosis remains poor. In recent years, antibody therapies have shown promising prospects against malignancy. This review focuses on the advances in antibody therapies in SCLC. Although the results of pembrolizumab, nivolumab, ipilimumab, and rovalpituzumab tesirine are inspiring, all of the clinical trials on these drugs are phase I/II and have been verified for further phase III clinical trials. It was demonstrated that chemotherapy in combination with bevacizumab can improve the progression-free survival (PFS) in phase III trials. The insulin-like growth factor-1 receptor (IGF-1R) is associated with a poor prognosis in SCLC, while the anti-IGF-1R monoclonal antibody figitumumab has a potential therapeutic value. Tarextumab, an antibody that blocks both Notch2 and Notch3 signaling, in combination with etoposide and platinum (EP) in patients with untreated extensive-stage SCLC, proved to be well-tolerated and showed dosedependent anti-tumor activity. The therapeutic effect of sacituzumab govitecan, BW-2 and lorvotuzumab mertansine in SCLC warranted further evaluation. Bec2/BCG as an adjuvant vaccination in patients with limited-disease SCLC could not improve the survival, PFS, or quality of life. Thus, clinical studies are essential to confirm the anti-tumor efficacy of trastuzumab in SCLC.

ADVL1522: A phase 2 study of IMGN901 (lorvotuzumab mertansine; IND# 126953, NSC# 783609) in children with relapsed or refractory Wilms tumor, rhabdomyosarcoma, neuroblastoma, pleuropulmonary blastoma, malignant peripheral nerve sheath tumor (MPNST), and synovial sarcoma: A Children's Oncology Group study.

10537 Background: Lorvotuzumab mertansine (IMGN901; LM) is an antibody-drug conjugate, linking anti-mitotic agent (DM1) to an anti-CD56 antibody. Preclinical data show effects in Wilms tumor (WT), rhabdomyosarcoma (RMS), and neuroblastoma (NBL). Synovial sarcoma (SS), MPNST and pleuropulmonary blastoma (PPB) also express CD56. A phase 2 trial assessing the efficacy and tolerability of LM administered at the adult recommended phase 2 dose (RP2D) was conducted in children with relapsed tumors. Methods: LM (110 mg/m2/dose) was administered IV on days (d) 1 and 8 of 21 d cycles, with dexamethasone pre-medication. The tolerability of LM was assessed in 6 patients prior to trial activation group-wide. Dose limiting toxicity (DLT) was assessed using CTCAE. Response was assessed by RECIST. Pharmacokinetics (PK) were obtained during cycle 1. Peripheral blood CD56-positive cells were measured d1 and d8 pre-dose. Tumor CD56 expression by immunohistochemistry in archival tissue was scored (0-3+). Results: Sixty-two patients were enrolled. The median (range) age was 14.3 y (2.8–29.9); 35 were male. Diagnoses included WT (17), RMS (17), NBL (12), SS (10), MPNST (5) and PPB (1). One patient was ineligible due to lack of measurable disease. Of 61 eligible patients, 47 were evaluable for toxicity, 50 for response, 50 for tumor CD56 expression; and 18 consented to optional PK. Five patients experienced 9 DLTs: hyperglycemia (1), colonic fistula (1) with perforation (1), nausea (1) with vomiting (1), increased ALT (2 in cycle 1; 1 in cycle 2 with increased AST (1)). Non-dose limiting toxicities (Grade ≥3) attributed to LM included lymphopenia, anemia, vomiting, dehydration, hypokalemia, hyperuricemia, hypophosphatemia. Mean DM1 Cmax, t1/2 and AUC0-∞values were 922 ng/ml, 33 h and 27400 ng/ml*h, respectively. Tumor CD56 expression was 0 (8%), 1+(4%), 2+(12%), 3+(76%). LM and CD56 antibody PK, and response, will be reported. Conclusions: LM (110 mg/m2) is tolerated in children at the adult RP2D. Clinical trial information: NCT 02452554.

Harnessing the Immune System Against Leukemia: Monoclonal Antibodies and Checkpoint Strategies for AML.

Acute myeloid leukemia (AML) is the most common leukemia among adults and is associated with a poor prognosis, especially in patients with adverse prognostic factors, older age, or relapsed disease. The last decade has seen a surge in successful immune-based therapies in various solid tumors; however, the role of immune therapies in AML remains poorly defined. This chapter describes the rationale, clinical data, and toxicity profiles of immune-based therapeutic modalities in AML including naked and conjugated monoclonal antibodies, bispecific T-cell engager antibodies, chimeric antigen receptor (CAR)-T cells, and checkpoint blockade via blockade of PD1/PDL1 or CTLA4. Monoclonal antibodies commonly used in AML therapy target highly expressed "leukemia" surface antigens and include (1) naked antibodies against common myeloid markers such as anti-CD33 (e.g., lintuzumab), (2) antibody-drug conjugates linked to either, (a) a highly potent toxin such as calicheamicin, pyrrolobenzodiazepine, maytansine, or others in various anti-CD33 (gemtuzumab ozogamicin, SGN 33A), anti-123 (SL-401), and anti-CD56 (lorvotuzumab mertansine) formulations, or (b) radioactive particles, such as 131I, 213Bi, or 225Ac-labeled anti-CD33 or CD45 antibodies. Novel monoclonal antibodies that recruit and promote proximity-induced cytotoxicity of tumor cells by T cells (bispecific T-cell engager [BiTE] such as anti CD33/CD3, e.g., AMG 330) or block immune checkpoint pathways such as CTLA4 (e.g., ipilimumab) or PD1/PD-L1 (e.g., nivolumab) unleashing the patients T cells to fight leukemic cells are being evaluated in clinical trials in patients with AML. The numerous ongoing clinical trials with immunotherapies in AML will improve our understanding of the biology of AML and allow us to determine the best approaches to immunotherapy in AML.

Phase 1/2 Study of the CD56-Targeting Antibody-Drug Conjugate Lorvotuzumab Mertansine (IMGN901) in Combination With Carboplatin/Etoposide in Small-Cell Lung Cancer Patients With Extensive-Stage Disease

IntroductionThis trial assessed the safety and efficacy of LM in combination with carboplatin/etoposide therapy compared to carboplatin/etoposide treatment alone in patients with previously untreated extensive-disease small-cell lung cancer (ED-SCLC). Patients and MethodsA run-in phase 1 stage was used to determine the recommended phase 2 dose and characterize the dose-limiting toxicities of LM in combination with carboplatin/etoposide followed by LM alone in patients with CD56-positive solid tumors. In phase 2, chemotherapy-naive ED-SCLC patients were randomized 2:1 to carboplatin AUC (area under the plasma concentration vs. time curve) of 5 day 1 + etoposide 100 mg/m2 days 1 to 3 plus LM (arm 1) or alone (arm 2). ResultsIn the phase 1 study (n = 33), a dose of LM at 112 mg/m2 with carboplatin/etoposide was identified as the recommended phase 2 dose. However, because of an increased incidence of peripheral neuropathy events during early phase 2, this dose was reduced to 90 mg/m2. In phase 2, a total of 94 and 47 evaluable patients were assigned to arms 1 and 2, respectively. No difference in median progression-free survival was observed between arms 1 and 2 (6.2 vs. 6.7 months). The most common treatment-emergent adverse event leading to discontinuation was peripheral neuropathy (29%). A total of 21 patients had a treatment-emergent adverse event leading to death (18 in arm 1 and 3 in arm 2); for 10 individuals, this was an infection (pneumonia or sepsis) deemed to be related to the study drug. ConclusionThe combination of LM plus carboplatin/etoposide did not improve efficacy over standard carboplatin/etoposide doublet therapy in ED-SCLC patients and showed increased toxicity, including a higher incidence of serious infections with fatal outcomes.

Management of Multiple Myeloma with Second-Generation Antibody-Drug Conjugates.

The antibody-drug conjugate (ADC) is a combination of a cytotoxic agent and monoclonal antibodies (mAbs) through a stable specialized chemical linker. After ADC binds to the target antigen, the conjugate is internalized and toxin is released, leading to the death of a target cell. Lorvotuzumab mertansine, indatuximab ravtansine, and milatuzumab-doxorubicin are currently under clinical development for use in multiple myeloma (MM). Preliminary data from recent studies indicate that these agents induce responses in patients with relapsed and/or refractory MM and have an acceptable safety profile.

Lorvotuzumab mertansine, a CD56-targeting antibody-drug conjugate with potent antitumor activity against small cell lung cancer in human xenograft models

Lorvotuzumab mertansine (LM) is an antibody-drug conjugate composed of a humanized anti-CD56 antibody, lorvotuzumab, linked via a cleavable disulfide linker to the tubulin-binding maytansinoid DM1. CD56 is expressed on most small cell lung cancers (SCLC), providing a promising therapeutic target for treatment of this aggressive cancer, which has a poor five-year survival rate of only 5–10%. We performed immunohistochemical staining on SCLC tumor microarrays, which confirmed that CD56 is expressed at high levels on most (~74%) SCLC tumors. Conjugation of lorvotuzumab with DM1 did not alter its specific binding to cells and LM demonstrated potent target-dependent cytotoxicity against CD56-positive SCLC cells in vitro. The anti-tumor activity of LM was evaluated against SCLC xenograft models in mice, both as monotherapy and in combination with platinum/etoposide and paclitaxel/carboplatin. Dose-dependent and antigen-specific anti-tumor activity of LM monotherapy was demonstrated at doses as low as 3 mg/kg. LM was highly active in combination with standard-of-care platinum/etoposide therapies, even in relatively resistant xenograft models. LM demonstrated outstanding anti-tumor activity in combination with carboplatin/etoposide, with superior activity over chemotherapy alone when LM was used in combinations at significantly reduced doses (6-fold below the minimally efficacious dose for LM monotherapy). The combination of LM with carboplatin/paclitaxel was also highly active. This study provides the rationale for clinical evaluation of LM as a promising novel targeted therapy for SCLC, both as monotherapy and in combination with chemotherapy.

Lorvotuzumab mertansine: antibody-drug-conjugate for CD56⁺ multiple myeloma

Lorvotuzumab mertansine (LM) is an ADC composed of an anti CD56 humanized N901 monoclonal antibody conjugated via a stable disulfide linker to the maytansinoid DM1. CD56 is expressed in up to 78% of multiple myelomas. LM displays antitumor activity in preclinical models of multiple myeloma. In a phase I study of MM, the MTD of single-agent LM was 112 mg/m². The dose-limiting toxicities were grade 3 fatigue and grade 3 acute, reversible, renal failure. 2 PRs and 4 MRs were observed at various dose levels starting at 60 mg/m². Building on the single agent experience, a phase II study of LM in combination with lenalidomide and dexamethasone was conducted. The optimal dose of LM was 75 mg/m² in the combination. The ORR was 56.4%. The most common treatment-related AE was peripheral neuropathy (PN), mostly grade 2 or less, with the majority of patients having a grade 1 PN at baseline. Continued evaluation of optimal dosing levels and schedules will be important to better define the utility of this promising treatment.

Initial testing (Stage 1) of the antibody-maytansinoid conjugate, IMGN901 (Lorvotuzumab mertansine), by the pediatric preclinical testing program

IMGN901 (lorvotuzumab mertansine) is an antibody-drug conjugate composed of a humanized antibody that specifically binds to CD56 (NCAM, neural cell adhesion molecule) and that is conjugated to the maytansinoid, DM1 (a microtubule targeting agent). IMGN901 and DM1-SMe (unconjugated DM1 as a mixed disulfide with thiomethane to cap its sulfhydryl group) were tested in vitro at concentrations ranging from 0.01 nM to 0.1 µM and 0.3 pM to 3 nM, respectively. IMGN901 was tested against a subset of PPTP solid tumor xenografts focusing on those with high CD56 expression.The combination of IMGN901 with topotecan was also evaluated. Neuroblastoma models expressed CD56 at or above the median expression level for all PPTP xenografts and cell lines. Neuroblastoma cell lines demonstrated relatively low sensitivity to DM1-SMe compared to other cell lines, but the sensitivity of neuroblastoma cell lines to IMGN901 was comparable to that of non-neuroblastoma cell lines. In vivo, objective responses were observed in 9 of 24 (38%) models including, three of seven neuroblastoma xenografts, and two of seven rhabdomyosarcoma xenografts. All xenografts with objective responses showed homogeneous high-level staining by IHC for CD56, but not all xenografts with homogenous high-level staining had objective responses. Combined with topotecan, IMGN901 demonstrated therapeutic enhancement against two of four neuroblastoma models. IMGN901 has anti-tumor activity against some CD56 expressing pediatric cancer models. High expression of CD56 is a biomarker for in vivo response, but resistance mechanisms to IMGN901 in some high CD56 expressing lines need to be defined.

1543TiP - Phase I/II Study to Assess the Safety, Pharmacokinetics (PK) and Efficacy of Lorvotuzumab Mertansine (LM, IMGN901) in Combination with Carboplatin/Etoposide in Patients with Solid Tumors Including Small-Cell Lung Cancer (SCLC)

ABSTRACT Purpose SCLC expresses CD56 almost universally. LM is a CD56-targeting antibody-drug conjugate. This study was initiated to evaluate LM for the treatment of SCLC when used in combination with carboplatin (C) and etoposide (E). Its phase 1 portion was designed to establish the recommended phase 2 dose (RP2D) of LM with C and E. PK data with the combination also was obtained. Methods Patients (pts) with advanced solid tumors were accrued to a standard 3 + 3 dose-escalation study design. Successive cohorts received escalating doses of LM IV on days 1 and 8 in combination with C IV on day 1 and E IV on days 1-3 every 21 days. LM PK was measured by an ELISA-based method. C and E levels were measured using optimized LC-MS/MS assays. PK parameters were determined by noncompartmental analysis. Results 33 patients (13M, median age = 57.3) were treated in 5 cohorts (2 using C AUC6; 3 using C AUC5) at LM doses ranging from 60-112 mg/m2. The RP2D was defined as LM 112 mg/m2 with C AUC5 and E 100 mg/m2. PK samples were analyzed for Cycle 1, first dose. At the RP2D, LM exposure and maximum concentration were similar to those observed in single-agent trials, with the t1/2 of LM approaching 1 day (24.2 hours). PK findings for C/E were similar to published reports (Oguri, 1988; D'Incalci, 1982) with the observed AUC of C = 5.1 ± 0.7 min*mg/mL and E = 6921 ± 1231 min*µg/mL. The most common treatment-related adverse events (AEs) were anemia, thrombocytopenia, nausea, peripheral neuropathy, decreased lymphocytes and neutrophils, and fatigue. The majority of related grade 3/4 AEs were cytopenias which, while known to occur with C/E regimens, typically have not been associated with LM monotherapy. Among 13 pts with SCLC accrued to phase 1, 6 (46%; 4 previously treated) achieved PR after at least one response assessment. Conclusion The combination is well tolerated with no apparent drug-drug interactions. Preliminary signs of activity have been observed in this predominantly pre-treated population. The randomized phase 2 portion of the study in chemo-naive patients with SCLC has opened to accrual. Updated data will be presented. Disclosure R. Guild: Employee of ImmunoGen, Inc. R. Mastico: Employee of ImmunoGen, Inc. All other authors have declared no conflicts of interest.

ADME of antibody-maytansinoid conjugates.

The concept of treating cancer with antibody-drug conjugates (ADCs) has gained momentum with the favorable activity and safety of trastuzumab emtansine (T-DM1), SAR3419, and lorvotuzumab mertansine (IMGN901). All three ADCs utilize maytansinoid cell-killing agents which target tubulin and suppress microtubule dynamics. Each ADC utilizes a different optimized chemical linker to attach the maytansinoid to the antibody. Characterizing the absorption, distribution, metabolism, and excretion (ADME) of these ADCs in preclinical animal models is important to understanding their efficacy and safety profiles. The ADME properties of these ADCs in rodents were inferred from studies with radio-labeled ADCs prepared with nonbinding antibodies since T-DM1, SAR3419, IMGN901 all lack cross-reactivity with rodent antigens. For studies exploring tumor localization and activation in tumor-bearing mice, tritium-labeled T-DM1, SAR3419, and IMGN901 were utilized. The chemical nature of the linker was found to have a significant impact on the ADME properties of these ADCs-particularly on the plasma pharmacokinetics and observed catabolites in tumor and liver tissues. Despite these differences, T-DM1, SAR3419, and IMGN901 were all found to facilitate efficient deliveries of active maytansinoid catabolites to the tumor tissue in mouse xenograft models. In addition, all three ADCs were effectively detoxified during hepatobiliary elimination in rodents.

Abstract C105: Pediatric Preclinical Testing Program (PPTP) Stage 1 evaluation of the CD56-targeting antibody-drug conjugate lorvotuzumab mertansine.

Abstract Introduction: Lorvotuzumab mertansine (LM) is a conjugate consisting of the cytotoxic maytansinoid, DM1, covalently linked to the humanized monoclonal antibody lorvotuzumab, which selectively binds to CD56 (NCAM, neural cell adhesion molecule). LM is currently in clinical trials for patients with CD56-positive cancers [e.g., small-cell lung cancer (SCLC), multiple myeloma, and Merkel cell carcinoma]. The activity of LM was evaluated against the in vitro and in vivo panels of the Pediatric Preclinical testing Program (PPTP). Methods: LM and its cytotoxic moiety L-DM1-SMe were tested against the PPTP's in vitro cell line panel at concentrations ranging from 0.01 nM to 0.1 μM using the PPTP's standard 96 hour exposure period. LM was tested against a subset of PPTP solid tumor xenografts at a dose of 15 mg/kg by the intravenous route using a weekly × 3 schedule with a total planned testing and observation period of 6 weeks. Models were selected for testing based on their CD56 expression levels. Results: The relative IC50 (rIC50) for LM and L-DM1-SMe were 35 nM and 2 nM, respectively. The two agents had very distinctive activity patterns, with LM showing its greatest activity against the neuroblastoma panel, and with L-DM1-SMe showing its highest activity against the ALL panel. L-DM1-SMe showed 79-fold greater potency against the ALL panel (median rIC50 1.1 nM) compared to the neuroblastoma panel (median rIC50 84 nM). By contrast, LM showed 1.7-fold greater potency against the neuroblastoma panel (median rIC50 32 nM) compared to the ALL panel (median rIC50 53 nM). The cell lines of the neuroblastoma panel had NCAM (CD56) expression at or above the median expression level for all PPTP xenografts and cell lines, and these cell lines demonstrated corresponding high levels of sensitivity to LM compared to L-DM1-SMe. The converse was true for the ALL cell lines, which had low NCAM (CD56) expression and low sensitivity to LM compared to L-DM1-SMe. In vivo, LM induced significant differences in EFS distribution compared to control in 15 of 18 (83%) of the evaluable solid tumor xenografts, including all 7 neuroblastoma xenografts. Objective responses were observed in 6 of 18 (33%) solid tumor xenografts [2 complete responses (CR) and 4 maintained CR (MCR)]. CR/MCR responses were observed for 3 of 7 neuroblastoma xenografts and 2 of 5 rhabdomyosarcoma xenografts. The other MCR observed was for the Wilms tumor xenograft KT-10. Each of the 6 xenografts achieving CR or MCR responses showed homogeneous staining by IHC for NCAM (CD56) with expression levels of 3 or 3+ (excepting NB-1643 which showed 2–3 level homogeneous staining). However, other xenografts also showed 3 or 3+ homogeneous staining but did not show tumor regression in response to LM treatment. Comparison of LM in vivo activity to that previously described for vincristine showed that neuroblastoma xenografts with data for both agents were more responsive to LM than to vincristine. Conclusions: LM shows target-directed activity in vitro and promising activity in vivo against CD56-expressing childhood cancers. Combination testing with topotecan is planned for the neuroblastoma panel to take advantage of previously reported synergistic interactions for topoisomerase-I inhibitors administered with microtubule-targeting agents (Cancer Chemother Pharmacol 2001:47; 211–21). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C105.

Abstract B195: Lorvotuzumab mertansine displays favorable pharmacokinetics and tumor delivery in mouse models.

Abstract Lorvotuzumab mertansine (LM) is an antibody-drug conjugate consisting of three components: a monoclonal antibody, lorvotuzumab, that binds specifically to the CD56 antigen expressed on several types of cancers; a potent maytansinoid cell-killing agent, DM1; and a linker, SPP, that connects the two via a hindered disulfide bond. LM is currently in clinical testing for the treatment of CD56-positive tumors with encouraging results reported (Berdeja et al., ASCO 2011, Woll et al., ASCO 2011). The linker component is key parameter that may be optimized during the preclinical development of an ADC. In addition of the SPP/DM1 linker/maytansinoid combination that was selected for LM, several other combinations were evaluated including SPDB/DM4, which results in a more hindered disulfide link and SMCC/DM1, which results in an uncleavable thioether link. In in vivo studies, these alternative designs were found to offer no efficacy advantage over the SPP/DM1 design, despite the fact that they have extended time in plasma circulation. Besides efficacy, the other important determinant of therapeutic window is tolerability, posing the question of whether the more readily cleavable SPP/DM1 link results in the formation of maytansinoid catabolites likely to increase toxicity. To examine this possibility and to investigate the efficiency of tumor delivery, we conducted experiments using tumor- and non-tumor-bearing mice administered with [3H]LM or LM. We extracted, identified, and quantified the [3H]maytansinoids from tumor tissue and plasma. We also purified and characterized LM and its degradation products from mouse plasma using affinity capture with antigen immobilized on beads and LC/MS. High levels of the active maytansinoid catabolites, lysine-SPP-DM1 and DM1, were found in the tumor tissues, consistent with the robust antitumor activity of LM observed in xenograft models. The plasma samples were found to contain low levels of S-cysteinyl-DM1, suggesting that cysteine can slowly reduce LM and displace the DM1 via thiol-disulfide exchange. Observation of lorvotuzumab-SPP-cysteine from plasma by LC/MS provides further support for this exchange. We synthesized S-cysteinyl-DM1 and found it to have much lower cytotoxicity than uncharged maytansinoids in cell-based viability assays. Thus, slow degradation of LM in plasma results primarily in the release of a maytansinoid catabolite with low cytotoxic potency. The finding of highly potent maytansinoid catabolites at tumor sites in in vivo models following LM administration combined with the determination that the predominant maytansinoid found in the plasma at low levels is the relatively non-toxic S-cysteinyl-DM1 catabolite is consistent with the promising efficacy and safety profile seen with LM in the clinic. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B195.

Efficacy results from a phase I study of lorvotuzumab mertansine (IMGN901) in patients with CD56-positive solid tumors.

e13582 Background: Lorvotuzumab mertansine is a conjugate of the cytotoxic maytansinoid, DM1, and the CD56-binding antibody, lorvotuzumab, and is designed to bind to and kill CD56-expressing cancer...

Abstract 1781: Lorvotuzumab mertansine (IMGN901) in combination with standard-of-care paclitaxel/carboplatin therapy is highly active in a preclinical xenograft model of ovarian cancer

Abstract The CD56-binding antibody-maytansinoid conjugate, lorvotuzumab mertansine (IMGN901), is currently being evaluated as monotherapy in patients with CD56-positive solid tumors including ovarian cancer, SCLC, and Merkel cell carcinoma. Encouraging results have recently been reported for this clinical trial, including 3 objective responses in second-line or later use (Woll, et al., ESMO 2010). CD56 is expressed on approximately 57% of ovarian cancers, supporting the clinical investigation of lorvotuzumab mertansine for this malignancy. Lorvotuzumab mertansine has been shown to be active as a single-agent against CD56-positive ovarian xenograft tumors, including OVCAR-3 and COLO 720E (Whiteman, et al., AACR 2008). Despite the high response rate of ovarian cancer to the standard-of-care first-line paclitaxel/carboplatin chemotherapy (approximately 60%), more than 80% of patients will relapse within 24 months of starting this treatment. Although advances in diagnosis and treatment have improved outcomes, the 5-year overall survival rate for ovarian cancer is only about 45%. Consequently, there is an unmet clinical need for treatments achieving long-term responses as first-line or second-line therapies for ovarian cancer. The possibility of achieving durable responses with combination of lorvotuzumab mertansine plus paclitaxel/carboplatin therapy was investigated in a preclinical model of ovarian cancer. The activity of lorvotuzumab mertansine in combination with the standard-of-care paclitaxel/carboplatin therapy was evaluated against COLO 720E ovarian xenografts in mice. The two dose levels of paclitaxel (10 or 20 mg/kg weekly × 3) plus carboplatin (100 mg/kg single injection) evaluated without lorvotuzumab mertansine were both active in this model, resulting in complete tumor regressions (CR) in 1 of 6 and 2 of 6 mice, respectively, with all tumors recurring during the study. Lorvotuzumab mertansine administered at a dose of 13 mg/kg weekly × 3 was active as a single agent, resulting in a CR in 1 of 6 mice which recurred during the study. Combination of lorvotuzumab mertansine with either dose level of paclitaxel/carboplatin resulted in CRs in all mice (6 of 6 mice/group), with no tumor recurrence during the study period (123 days). The long-term CRs observed in a preclinical model of ovarian cancer suggest lorvotuzumab mertansine in combination with standard-of-care agents would be a promising combination treatment regimen to evaluate in the clinic due to its potential to achieve an increased response rate and more durable responses compared with standard-of-care agents alone, which could represent a significant therapeutic benefit to ovarian cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1781. doi:10.1158/1538-7445.AM2011-1781

Abstract 770: Lorvotuzumab mertansine (IMGN901) immune effector activity and its effect on human NK cells

Abstract Lorvotuzumab mertansine, or IMGN901, is a conjugate consisting of the cytotoxic maytansinoid, DM1, covalently linked to the monoclonal antibody, lorvotuzumab, which selectively targets CD56 (also called neural cell adhesion molecule or NCAM). This conjugate is currently being evaluated in clinical trials for the treatment of CD56+ solid tumors and multiple myeloma. It is able to inhibit tumor cell growth by disruption of microtubule dynamics through delivery of its cytotoxic DM1 payload; however, other potential cell killing mechanisms, such as the immune effector activity of its antibody component, have not been fully investigated. Herein, we report on the immune effector activity of the lorvotuzumab antibody and the lorvotuzumab mertansine conjugate and their effect on the function of CD56+ human primary NK cells in vitro. To investigate the effector activity of the antibody, lorvotuzumab was incubated with CD56+ tumor target cells in the presence of rabbit complement or purified human primary NK cells. The results show that this antibody fails to mediate complement dependent cytotoxicity (CDC) but induces antibody-dependent NK cell-mediated cytotoxity (ADCC) in dose-dependent manner. The complete conjugate showed ADCC activity comparable to lorvotuzumab alone, suggesting that DM1 conjugation did not alter the interaction between the Fc domain of the antibody and NK cell's Fc receptor. Since human primary NK cells express CD56, albeit at a low level, we tested whether lorvotuzumab mertansine or its antibody component could negatively impact the function of NK cells. The results demonstrate that incubation with this antibody or with this conjugate has no effect on rituximab-mediated ADCC activity of the NK cells. Furthermore, overnight exposure of human primary NK cells with lorvotuzumab mertansine did not change rituximab-mediated ADCC activity. In conclusion, the lorvotuzumab antibody has ADCC activity that is retained after DM1 conjugation. Furthermore, neither lorvotuzumab nor its DM1 conjugate, appear to affect the ability of NK cells (which are CD56+) to mediate ADCC through another antibody. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 770. doi:10.1158/1538-7445.AM2011-770

Immunoconjugates Against Solid Tumors: Mind the Gap

The objective of immunoconjugate development is to combine the specificity of immunoglobulins with the efficacy of cytotoxic molecules. This therapeutic approach has been validated in hematologic malignancies; however, several obstacles to achieving efficacy in treating solid tumors have been identified. These include insufficient specificity of targets and poor antibody delivery, most specifically to the tumor core. Heterogeneous antigen expression, imperfect vascular supply, and elevated interstitial fluid pressure have been suggested as the factors responsible for the poor delivery of antibodies. Promising immunoconjugates are in development: immunoconjugates targeting the prostate-specific membrane antigen, trastuzumab-DM1, lorvotuzumab mertansine, and SS1P. Advances in cancer biology and antibody engineering may overcome some of the challenges. New small antibody formats, such as single-chain Fv, Fab, and diabodies, may improve penetration within tumor masses. Nevertheless, the cost of treatment might require justification in terms of demonstrable improvement in quality of life in addition to efficacy; further economic evaluation might be necessary before this approach can replace the current standards of care in clinical practice.