Safety, tolerability, and preliminary activity of IMGN529, a CD37-targeted antibody-drug conjugate, in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: a dose-escalation, phase I study

Non-Hodgkin lymphoma (NHL) represents a heterogeneous collection of distinct malignancies of the lymphatic system, each associated with their own pathological features and clinical outcomes [1]. Approximately 85% of NHL diagnoses are of B-cell origin; the most frequent histological subtypes include diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), marginal zone lymphoma (MZL), and mantle cell lymphoma (MCL). Since its introduction into B-cell lymphoma management two decades ago, the anti-CD20 antibody rituximab has improved survival outcomes for patients with DLBCL, FL, and MCL, as well as in other subsets [2]. Indeed, the clinical success of rituximab has served as a paradigm for tailored therapeutic approaches in the treatment of B-cell malignancies and targeting of alternative cell surface antigens (e.g., CD19, CD30) continues to be an actively pursued therapeutic area [2]. An urgent need for improved therapeutic options still exists, particularly for patients with aggressive-histology lymphomas (such as DLBCL) in the refractory and/or relapsed settings, as outcomes for these individuals remain poor [3].

One promising target is the tetraspanin CD37, a transmembrane protein whose exact physiological function(s) are yet to be defined, although there is evidence to suggest it is involved in immune cell proliferation and survival [4, 5]. In normal tissues, CD37 shows a restricted distribution pattern with expression limited to lymphoid tissues - most frequently on the surface of B-cells from the pre-B through the peripheral mature stages of differentiation but absent on early progenitor and terminally differentiated plasma cells [6, 7]. Importantly, CD37 is highly expressed on malignant B-cells, including most subtypes of NHL [8, 9]. This differential expression profile identified CD37 as a candidate for the development of novel therapeutics. A limited number of CD37-targeting approaches have been explored to date, including radioimmunotherapy with a radiolabeled anti-CD37 antibody (¹³¹I–MB-1) [10, 11], a CD37-binding small immunopharmaceutical protein (TRU-016) [12], and a Fc-engineered antibody (BI836826) [13], with the latter two agents both exhibiting antibody-dependent cell-mediated cytotoxicity (ADCC) and apoptosis-inducing abilities.

Antibody-drug conjugate (ADC) technology provides targeted delivery of cytotoxic agents via linkage to monoclonal antibodies directed against tumor-associated antigens [14]. Importantly, this approach has been clinically validated with four ADCs currently approved for use in human cancer: brentuximab vedotin, a conjugate of an anti-CD30 antibody with monomethyl auristatin E (MMAE) [15] that is approved for relapsed Hodgkin lymphoma, systemic anaplastic large-cell lymphoma, and most recently for subtypes of cutaneous anaplastic large-cell lymphoma; ado-trastuzumab emtansine (T-DM1), a conjugate of trastuzumab with the maytansinoid DM1 [16], used to treat HER2-positive metastatic breast cancer; and two calicheamicin-bearing conjugates, inotuzumab ozogamicin and gemtuzumab ozogamicin, CD22- and CD33-targeting ADCs approved to treat B-cell precursor acute lymphoblastic leukemia or acute myeloid leukemia, respectively. IMGN529 is an ADC comprised of a humanized anti-CD37 monoclonal antibody linked to DM1, which combines the intrinsic proapototic and effector activities of its antibody component with the potent cytotoxic activity of its payload [17]. High affinity binding of IMGN529 to CD37 followed by its internalization results in the intracellular release and accumulation of DM1, which in turn promotes disruption of microtubule assembly, G2/metaphase arrest, and ultimately apoptosis [18]. In preclinical studies, IMGN529 has shown robust antitumor activity in CD37-positive NHL models [17, 19], thus providing a rationale for its clinical evaluation as targeted therapy for the treatment of B-cell malignancies.

This first-in-human, phase I study of IMGN529 monotherapy was designed to assess the overall safety, pharmacokinetics, and preliminary activity of this novel investigational agent in a dose-finding cohort of patients with relapsed or refractory B-cell NHL.

This study established the MTD of IMGN529 as 1.4 mg/kg every 3 weeks, with growth factor support. The dose of 0.7 mg/kg (without growth factor support) every 3 weeks was selected for phase 2 evaluation, with a safety run-in period, in combination with rituximab in patients with relapsed or refractory B-cell NHLs.

The majority of treatment-emergent adverse events, including fatigue, pyrexia, nausea, and diarrhea, were primarily grade 1–2. At low doses (≤ 0.4 mg/kg) without prophylaxis, early-onset grade 3–4 neutropenia and febrile neutropenia emerged as toxicities of note. Peri-infusional steroid use decreased their incidence and permitted further escalation to 1.0 mg/kg. At this level, patients showed delayed-onset febrile neutropenia and neutropenia - which prompted the introduction of granulocyte growth factor prophylaxis. This facilitated neutrophil count recovery and enabled escalation sufficient to declare an MTD. Overall, neutropenia, febrile neutropenia, and thrombocytopenia were the most frequently observed grade ≥ 3 adverse events and the primary DLTs observed. The underlying mechanisms of these myelosuppressive effects are likely linked to off-target effects derived from the microtubule-disrupting function of the DM1 payload in IMGN529. Neutropenia is more consistently observed in ADCs that contain a MMAE payload [21], including brentuximab vedotin [22], and was recently identified as a key toxicity of polatuzumab vedotin, a CD79b-targeting ADC, as part of a dose-escalation study in B-cell NHL patients [23]. Thrombocytopenia has been reported for other DM1-containing conjugates, however is more widespread for calicheamicin-utilizing ADCs [21]. Indeed, the incidence and severity observed in this study compare favorably to those seen in NHL patients treated with inotuzumab ozogamicin, a CD22-targeted ADC containing calicheamicin, where these events were the leading cause of serious adverse events, dose modifications, and discontinuations [24]. The remaining DLT, peripheral neuropathy, was observed in one patient treated at 0.8 mg/kg; however due to an overall low frequency across the safety population, the relevance of this potential toxicity remains undefined.

Pharmacokinetic analysis revealed that IMGN529 exposure did not increase proportionally with dose over the entire dose range during cycle 1. Lower doses (<0.8 mg/kg) showed increased clearance and decreased terminal half-life relative to doses above 1.0 mg/kg, consistent with TMDD [25]. IMGN529 exhibited a dose-proportional increase in AUC_∞ at doses ≥1.0 mg/kg. Maximal IMGN529 concentrations increased proportionally over the entire dose range, and the volume of distribution was consistent with plasma volume at all doses.

Although only moderate clinical activity was seen across the heterogeneous NHL population, the signals of efficacy observed in patients with DLBCL are encouraging, particularly given that all had advanced disease and were heavily pretreated. While stable disease was most commonly seen in indolent and intermediate types of lymphoma (FL and MCL), the confirmed tumor responses tended to cluster in patients diagnosed with DLBCL. A lack of available tumor tissue precluded complete biomarker analyses and thus no correlations between activity and cell of origin classification or CD37 expression could be determined. However, immunohistochemical detection of CD37 was seen on all evaluable samples. Moreover, it is notable that the patient who achieved a complete response had non-GCB DLBCL, a molecular subtype that confers a poorer prognosis than those of GCB origin [26], as well as high CD37 expression. The duration of response for the additional DLBCL responders lasted as long as 8.4 months, providing further evidence that IMGN529 has meaningful activity in patients with refractory, aggressive disease. Importantly, our findings validate CD37 as a rational target for therapeutic intervention in DLBCL. To date, the initial human evaluations of the CD37-targeting agent TRU-016 have been conducted either as monotherapy in patients with chronic lymphocytic leukemia (CLL) or as part of combinations in indolent lymphomas [27, 28] and therefore the efficacy results seen here cannot be directly compared to those studies. Currently, there is another CD37-targeting ADC in development, AGS67E, which comprises MMAE conjugated to an antibody component that lacks the intrinsic apoptotic and ADCC activity present in IMGN529 [29]. A phase 1 study of AGS67E monotherapy in patients with relapsed/refractory NHL and CLL is ongoing and final results are not yet available; however interim reports have similarly identified objective responses in DLBCL patients as part of that trial [30]. Of note, delayed-onset neutropenia was also identified as a dose-limiting toxicity in the study, which similarly required growth factor support in order to allow escalation to proceed.

Preliminary biomarker analyses were additionally performed using a subset of 33 patient samples that were available for CD37 expression staining, two-thirds of which were found to express the antigen at high levels. Based on the small sample size, however, no statistically relevant relationships between CD37 expression and likelihood of response were detected. Further efforts are therefore needed to identify any predictive or prognostic biomarkers associated with IMGN529 treatment.

Overall, the results of this study support the continued evaluation of IMGN529 as a novel CD37-targeting therapeutic in NHL, based on its manageable safety profile and encouraging signs of clinical efficacy, particularly in patients with DLBCL. In this regard, the clinical exploration of the IMGN529 in combination with rituximab has commenced, with a Phase 2 study in patients with relapsed or refractory B-cell lymphoma currently underway (NCT02564744).