Brentuximab vedotin (Adcetris®, SGN-35)
Brentuximab (BV) is composed of an anti-CD30 chimeric IgG1 mAb conjugated to MMAE via a protease-cleavable linker [
48]. CD30 is a tumor necrosis factor (TNF) receptor superfamily member, characteristically expressed on the surface of Reed–Sternberg cells in Hodgkin lymphoma (HL) [
49], anaplastic large cell lymphoma (ALCL) cells, and a subset of cutaneous T cell lymphoma (CTCL) cells, with limited expression on normal cells [
50].
Single-agent BV has been approved by the US FDA in 2011 for the treatment of HL after failure of autologous stem cell transplantation (ASCT) or after failure of at least two prior multiagent chemotherapy regimens [
8,
49,
51,
52] (Table
1). In a pivotal phase II trial (NCT00848926), 102 patients with relapsed/refractory (R/R) HL who failed ASCT were treated with intravenous BV 1.8 mg/kg every 3 weeks at a maximum of 16 cycles in the absence of disease progression or unacceptable toxicity. The overall response rate (ORR) was 75% with 34% complete remission (CR) and the median duration of response (DOR) was 6.7 months. The most common treatment-emerging adverse events (TEAE) were peripheral sensory neuropathy (42%), nausea (35%), fatigue (34%), and neutropenia (19%). Fifty-five percent of patients experienced grade ≥ 3 AEs (SAE), majority of which included neutropenia (20%) and peripheral sensory neuropathy (8%). Most of these AEs are manageable with dose reductions and/or delays [
8,
53]. At the 5-year follow-up, the overall survival (OS) and progression-free survival (PFS) rate for all patients were 41% and 22% respectively. The estimated median OS and PFS were 40.5 and 9.3 months respectively, suggesting long-term disease control provided by single-agent BV [
54]. However, many patients still eventually developed resistance partially because of the upregulation of multidrug resistance pump (MDR1), a drug export pump. Currently, a phase I trial (NCT03013933) is investigating the combination of BV and cyclosporine (CsA), an MDR1 inhibitor, for R/R HL. The interim result was encouraging, showing a 67% ORR (33 % CR) and a manageable toxicity profile at the maximum tolerated dose (MTD) [
55].
Table 1
FDA approved antibody-drug conjugates for B cell malignancies and multiple myeloma
Brentuximab vedotin (Adcetrix®) | CD30 | R/R HL | - 1.8 mg/kg (maximum 180 mg) - Every 3 weeks until disease progression or unacceptable toxicity | 2011 |
Frontline stage III & IV HL (+ AVD) | - 1.2 mg/kg (maximum 120 mg) combined with chemotherapy - Every 2 weeks until a maximum of 12 doses, disease progression, or unacceptable toxicity | 2018 |
Post-ASCT consolidation for HL | - 1.8 mg/kg (maximum 180 mg) - Initiate within 4–6 weeks post-ASCT or upon recovery from ASCT - Every 3 weeks until a maximum of 16 cycles, disease progression, or unacceptable toxicity | 2015 |
R/R systemic ALCL | - 1.8 mg/kg (maximum 180 mg) - Every 3 weeks until disease progression or unacceptable toxicity | 2011 |
R/R PTCL (+ CHP) | - 1.8 mg/kg (maximum 180 mg) combined with chemotherapy - Every 3 weeks with each cycle of chemotherapy for 6 to 8 doses | 2018 |
R/R CTCL | - 1.8 mg/kg (maximum 180 mg) - Every 3 weeks until a maximum of 16 cycles, disease progression, or unacceptable toxicity | 2017 |
Inotuzumab ozogamicin (Besponsa®) | CD22 | R/R B-cell ALL | - Cycle 1 (21 day-cycle): 1.8 mg/m2 [day 1 (0.8 mg/m2), day 8 (0.5 mg/m2), and day 15 (0.5 mg/m2)] - Subsequent cycles (28 day-cycle): 1) Patients who have achieved CR or CRi: 1.5 mg/m2 [day 1 (0.5 mg/m2), day 8 (0.5 mg/m2), and day 15 (0.5 mg/m2)] per cycle 2) Patients who have not achieved CR or CRi: repeat cycle 1 - Duration: 1) Patients proceeding to ASCT: 2 cycles 2) Patients not proceeding to ASCT: maximum 6 cycles | 2017 |
Moxetumomab pasudotox (Lumoxiti®) | CD22 | R/R HCL | - 0.04 mg/kg on days 1, 3, and 5 of each 28-day cycle. - Maximum of 6 cycles, disease progression, or unacceptable toxicity | 2018 |
Polatuzumab vedotin (Polivy®) | CD79b | R/R DLBCL (+ BR) | - 1.8 mg/kg per cycle, combined with BR - every 21 days for 6 cycles | 2019 |
BV plus bendamustine (BVB) has been studied as a salvage regimen for R/R HL with favorable toxicity profile in phase I/II trials. One study (NCT01657331) revealed that BVB achieved a 78% ORR in heavily pretreated HL patients. Grade 3 to 4 neutropenia were found in 25% of patients across the trial [
56]. Another study (NCT01874054) used BVB as the first salvage regimen for 55 HL patients who failed the frontline therapy. A better outcome was reported with a 92.5% ORR (73.6% CR) and a 62.6% estimated 2-year PFS. Further, 75.4% patients proceeded to ASCT. Most frequently reported SAEs included rash (16.3%), lymphopenia (10.9%), and hypotension (7.3%) [
57]. There is another ongoing trial (NCT01657331) that identified 23 out of 65 patients treated with BVB who experienced prolonged median PFS of more than 1 year [
58]. BV in combination with nivolumab (Nivo) represents another ongoing clinical trial for R/R HL. In the phase I/II trial (NCT02572167), BV + Nivo achieved 82% ORR and 61% CR, almost doubled the CR rate of BV monotherapy in the pivotal phase II trial. There were mostly grade 1 and 2 AEs: nausea (49%), fatigue (41%), infusion-related reactions (44%) [
59]. Currently, BVB and BV + Nivo are being compared in an ongoing phase II trial (NCT02927769).
BV is an effective option of consolidation therapy both before and after ASCT for HL at a high risk of relapse or progression. A randomized, double-blind, multinational, phase III trial (AETHERA, NCT01100502) enrolled 329 eligible patients to receive either 16 cycles of 1.8 mg/kg intravenous BV or placebo every 3 weeks, starting 30–45 days after transplantation. Median PFS was 42.9 months for patients in the BV group (
n = 165), significantly better than the 24.1 months in the placebo group (
n = 164) [
60]. There was continued benefit at 5-year follow-up, with PFS rate for patients receiving BV and placebo at 59% and 41% respectively [
61]. The toxicity profile mainly consisted of peripheral neuropathy (56%) and neutropenia (35%), with neutropenia (29%) being the most common SAE [
60]. Recently, a retrospective multicenter study revealed that chemo-refractory HL patients receiving BV prior to allogeneic SCT (AlloSCT) presented with a better outcome and a lower incidence of chronic graft versus host disease (GVHD) at 3-year follow-up compared to those without BV (PFS 53% vs. 33%; OS 62% vs. 44%; GVHD incidence 43% vs. 47%) [
62].
BV in combination with chemotherapy has been reported to optimize the frontline treatment of newly diagnosed advanced stage HL. This report was from the international randomized phase III trial (ECHELON-1, NCT01712490) which assigned patients with previously untreated stage III or IV classic HL to receive either BV (adcetris) plus doxorubicin, vinblastine, and dacarbazine (AAVD) (
n = 664) or doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) (
n = 670) [
51]. The outcome of the AAVD cohort appeared to be superior to the ABVD cohort in terms of the 2-year modified PFS (81.0% vs. 74.4%), which was further confirmed by sensitivity analysis, even though the response rate was not significantly different between the two cohorts: ORR (86% vs. 83%), CR (73% vs. 70%). Of note, patients receiving AAVD presented with a higher incidence of peripheral neuropathy (29% vs. 17%) but a lower incidence of pulmonary toxicity (< 1% vs. 3%) than patients receiving ABVD. Neutropenia (54% vs. 39%) was the most frequently encountered SAE in both cohorts. Prophylaxis with granulocyte colony-stimulating factor (G-CSF) effectively decreased the rate of neutropenia and febrile neutropenia [
51,
63].
BV plus etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone (BrECADD), a modified first-line treatment for advanced classical HL by incorporating BV was reported with an 88% CR rate and a more favorable toxicity profile (NCT01569204) [
64]. This BrECADD regimen is currently being compared to the standard BEACOPP chemotherapy in a phase III randomized trial (HD21, NCT02661503).
BV has been studied in a few subtypes of non-Hodgkin lymphoma (NHL), including systemic ALCL, an aggressive CD30
+ subtype of peripheral T cell lymphoma (PTCL). In a phase II multicenter trial (NCT00866047), 58 patients with systemic ALCL after failure of at least one prior multiagent chemotherapy regimen received intravenous BV 1.8 mg/kg every 3 weeks. Fifty (86%) patients achieved ORR, and 33 (57%) achieved CR [
65]. For all enrolled patients, the estimated 5-year OS and PFS were 60% and 39% respectively. Among those who achieved CR, the 5-year OS and PFS were 79% and 57% respectively. Of the 50 patients with an objective response, the median duration of response (DOR) was 25.6 months [
66]. In 2018, FDA approved BV in combination with cyclophosphamide, doxorubicin, and prednisone (CHAP) for the treatment of CD30-expressing PTCL including systemic ALCL, angioimmunoblastic T cell lymphoma, and PTCL not otherwise specified, based on the positive result of a randomized, double-blind phase III trial (ECHELON-2, NCT01777152). In this study, 452 PTCL patients were randomized to receive either CHAP or cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). The patients in the CHAP group had longer PFS (48.2 months vs. 20.8 months), a higher ORR (83% vs. 72%), and CR rate (68% vs. 56%). Most common AEs of CHAP recipients were nausea (46%), peripheral neuropathy (45%), neutropenia (38%), and diarrhea (38%), comparable to those of CHOP recipients. Neutropenia (35%) was the most common SAE [
67]. BV has also been investigated in cutaneous T cell lymphoma (CTCL). In a multicenter randomized phase III trial (ALCANZA, NCT01578499) that enrolled adult patients with CD30-positive mycosis fungoides or primary cutaneous ALCL who had received prior systemic therapy, patients receiving BV demonstrated more favorable outcome than those receiving conventional therapy (methotrexate or bexarotene): ORR lasting at least 4 months (56.3% vs. 12.5%), CR (16% vs 2%), and median PFS (17.2 vs. 3.5 months). A higher level of CD30 expression seemed to be associated with a better response to treatment with BV. There were mostly grade 1 to 2 AEs in BV-treated patients. Of note, the incidence of reported peripheral neuropathy (45%; grade ≥ 3: 5%) was much higher than that in patients receiving conventional therapy. Other common AEs included nausea (36%), diarrhea (29%), and fatigue (29%) [
68].
In addition, several studies suggested that BV could provide additional treatment options for patients suffering from R/R B-cell NHL [
69,
70]. In one phase II trial (NCT01421667) that enrolled 49 patients with heavily pretreated diffuse large B cell lymphoma (DLBCL), there was a 44% ORR with a 17% CR, and the DOR was 16.6 months [
69].
Inotuzumab ozogamicin (Besponsa®, CMC-544)
Inotuzumab ozogamicin (InO) is composed of a humanized anti-CD22 IgG4 mAb conjugated to calicheamicin via an acid-labile linker [
71]. CD22 is a B cell-restricted transmembrane sialoglycoprotein, present on the surface of mature B cells, and thought to be involved in signal transduction, B cell activation and regulation [
11,
71]. CD22 is also expressed by most B cell malignancies, including leukemic blasts in > 90% patients with B cell ALL, as well as chronic lymphocytic leukemia (CLL), NHL, and hairy cell leukemia (HCL) [
72,
73]. Therefore, CD22 represents an important therapeutic target for ALL and other B cell malignancies.
InO has been approved by the US FDA in 2017 for the treatment of R/R CD22-positive B cell ALL [
9,
10]. The approval was mainly based on a phase III, international, randomized trial (INO-VATE, NCT01564784) designed to compare single-agent InO with chemotherapy regimens as first or second salvage therapy for R/R ALL patients. Three hundred thwenty-six adult patients were randomized to receive either InO (
n = 164) or standard of care (SoC, intensive chemotherapy;
n = 162) [
74]. The CR/CR with incomplete hematologic recovery (CRi) rate was significantly higher in patients in the InO arm (73.8%) compared to those in the SoC arm (30.9%). Both PFS and OS were longer with InO than SoC: the median PFS was 5.0 vs. 1.7 months, the median OS was 7.7 vs. 6.2 months, and the 2-year OS rate was 22.8% vs. 10.0%. Subset analyses revealed that remission rates remained consistent for patients with Philadelphia chromosome-positive (Ph+) or -negative (Ph−) ALL. Interestingly, more patients in the InO arm proceeded directly to AlloSCT after achieving CR/CRi (39.6% vs. 10.5%), suggesting InO as an effective bridging therapy to transplantation [
75]. Besides, InO-treated patients reported a better quality of life than those receiving SoC [
76]. Frequent AEs reported by InO recipients were neutropenia (36%), thrombocytopenia (29%), anemia (18%), febrile neutropenia (16%), nausea (15%), and pyrexia (11%), with lower incidences than SoC recipients [
74]. However, there is a higher incidence of hepatotoxicity especially veno-occlusive disease (VOD) (14% vs. 2.1%), which is also the most common SAE found in InO recipients. Of note, among patients who proceeded to AlloSCT, 22% of InO recipients developed VOD after transplantation compared to only 3% of SoC recipients [
77]. In view of this risk, expert opinions recommended that for patients planning to receive AlloSCT, InO administration should be limited to two cycles. Transplantation conditioning regimens containing two alkylating agents or any concomitant hepatotoxic drugs should be avoided [
78]. Besides, patients receiving InO should also be monitored for prolonged QTc and tumor lysis syndrome. Interestingly, weekly low doses of InO has been revealed to result in less AEs than single-dose InO [
79]. Currently, there is an ongoing trial evaluating the efficacy of weekly low-dose InO for R/R CD22-positive ALL (NCT03094611).
In addition to monotherapy, InO has been studied in combination with chemotherapy for R/R B cell ALL. InO was added to the treatment cycles of mini-hyper-CVD (miniHCVD), which was a modified hyper-CVAD regimen (hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) with no anthracycline, whereas cyclophosphamide and dexamethasone were given at 50% dose reduction, methotrexate at 75% dose reduction, and cytarabine at 0.5 mg/m
2 for four doses [
80]. InO was added on day 3 of each cycle with 1.3 mg/m
2 in cycle 1 and 1 mg/m
2 in subsequent cycles. A phase II trial (NCT01371630) enrolled 59 patients with R/R B cell ALL receiving InO-miniHCVD. The regimen showed a 78% ORR (59% CR) and a minimal residual disease (MRD) negativity of 82% among responders. The median OS and PFS were 11 and 8 months respectively, and the 1-year overall OS and PFS rates were 46% and 40% respectively. Subset analysis showed that the OS rate was much higher in patients who were treated in first salvage than those in subsequent salvages. Notably, 44% patients proceeded to subsequent ASCT suggesting InO + miniHCVD as an option for bridging therapy. The most common SAEs reported were thrombocytopenia (81%) and infections (73%). VOD still occurred in 15% of patients [
81]. Even though InO + miniHCVD seemed to present with more favorable outcomes compared to the INO-VATE trial, further phase III studies are still warranted to ascertain the value of this combination therapy.
InO-miniHCVD has also been investigated as a frontline therapy in older patients (≥ 60 years) with newly diagnosed Ph− B cell ALL [
82]. A single-arm phase II trial (NCT01371630) conducted in MD Anderson Cancer Center first reported that InO-miniHCVD demonstrated robust activity (ORR 98%, CR 85%, 3-year OS 56%, and 3-year PFS 49%). Frequently reported SAEs were thrombocytopenia (81%), infections occurred during induction (52%) or consolidation (69%), hyperglycemia (54%), and hepatic events including VOD (33%) [
82]. In an attempt to further reduce toxicity and length of maintenance, blinatumomab (blina), a bispecific T cell-engaging antibody targeting both CD19 and CD3 [
83‐
86], was added to the regimen. This new regimen, InO-miniHCVD with or without blina, achieved a 98% ORR (87% CR) and a 54% 3-year OS according to the interim result of an ongoing phase II trial (NCT03249870), comparable to the previous one [
87]. A recently published retrospective propensity score analysis reported that older patients with newly diagnosed Ph− ALL who received InO-miniHCVD ± blina demonstrated better outcomes and lower risks than those who received hyper-CVAD (ORR 98% vs. 88%; 3-year OS 64% vs. 34%; early death 0% vs. 8%) [
88]. Currently, there is another ongoing trial examining combination of InO with hyper-CVAD as a frontline therapy for ALL patients (NCT03488225).
The development of InO in B cell lymphoma has made relatively less progress. Single-agent InO was administered to 81 patients with R/R B cell NHL, predominantly follicular lymphoma (FL), who failed rituximab, rituximab plus chemotherapy, or radioimmunotherapy in a phase II trial (NCT00868608). The study reported a 67% ORR, a 31% CR, and a median PFS of 12.7 months. Bone marrow suppression was reported with most frequently thrombocytopenia (74%) and neutropenia (56%). Of note, 58% of patients with AEs discontinued the treatment [
89]. InO combined with rituximab (R-InO) is thought to be a treatment option for patients with R/R B cell NHL who are not candidates for high-dose chemotherapy. One phase I/II trial (NCT00299494) reported that the R-InO regimen at MTD (1.8 mg/m
2 InO plus 375 mg/m
2 rituximab) yielded an 87% ORR for R/R FL and 74% ORR for R/R DLBCL. R-InO demonstrated a similar toxicity profile to the single-agent InO [
90]. A separate phase II trial (NCT00867087) reported only 29% ORR after 3 cycles of R-InO for patients with R/R DLBCL [
91]. However, a recent randomized phase III trial (NCT01232556) revealed that the outcome of the R-InO recipients appeared not to be superior to those receiving rituximab plus chemotherapy of bendamustine or gemcitabine in terms of ORR (41% vs. 44%), OS (35% vs. 37%), and PFS (19% vs. 17%) [
92]. Several clinical trials are exploring different new regimens. InO at 0.8 mg/m
2 combined with full dose of rituximab, cyclophosphamide, vincristine, and prednisolone (R-CVP) was reported safe and effective for CD22
+ R/R B cell NHL in a phase I trial (NCT01055496). The ORR was 84% with 24% CR. Subset analysis showed that ORR was 100% for patients with indolent lymphoma and 57% for those with aggressive histology. The toxicity profile was also similar to InO monotherapy [
93]. Currently, InO + R-CVP is being evaluated in patients with DLBCL not suitable for anthracycline-based chemotherapy in a phase II trial (NCT01679119). InO at 0.8 mg/m
2 plus full dose rituximab, gemcitabine, dexamethasone, and cisplatin (R-GDP) is a regimen proposed by another phase I trial (NCT01055496) for patients with R/R CD22
+ B cell NHL. The preliminary result was less encouraging (53% ORR; 20% CR) [
94].
Moxetumomab pasudotox (Lumoxiti®, CAT-8015)
Moxetumomab pasudotox (MP) is the second anti-CD22 ADC that comes into clinical practice. It has the Fv fragment of a recombinant murine mAb with higher affinity for CD22 than the parent compound [
95]. The fragment is genetically fused to a truncated form of
Pseudomonas aeruginosa exotoxin (PE38) [
96]. MP has been approved by the US FDA in September 2018 for the treatment of adult patients with R/R hairy cell leukemia (HCL) who have received at least two prior systemic therapies, including two courses of a purine analog or one course of rituximab or a BRAF inhibitor following a single course of a purine analog. The approval was mainly based on a pivotal, multicenter, open-label, single-arm trial (NCT01829711) that enrolled 80 patients who received 40 μg/kg MP intravenously on days 1, 3, and 5 every 28 days for a maximum of 6 cycles. The treatment led to a 75% ORR with 41% CR. Eighty-five percent of CR patients achieved MRD negativity. PFS was not yet reached at a median follow-up of 16.7 months. The median DOR for the MRD-positive patients was 5.9 months and has not been reached for MRD-negative patients [
97]. Elimination of MRD has been shown to be associated with prolonged CR duration [
98]. The most common treatment-emerging AEs (TEAE) were peripheral edema (39%), nausea (35%), fatigue (34%), and headache (33%). Serious AEs included hemolytic uremic syndrome (HUS) (8%) and capillary leak syndrome (CLS) (5%). Although four of HUS and two of CLS patients ended up with discontinuation of therapy, most of the above AEs were manageable with dose reduction and supportive care [
97,
99]. It was noted that antidrug titers increased after repeated administration of the ADC [
99]. Currently, a phase I trial (NCT03805932) is looking at whether the combination of MP and rituximab is safe and effective for R/R HCL. The development of MP for precursor cell lymphoblastic leukemia/lymphoma, NHL, and CLL has been discontinued [
99].
Polatuzumab vedotin (Polivy®, DCDTS4501A)
CD79b is a component of the B cell receptor (BCR) complex [
100]. It is a promising therapeutic target because of its restricted expression on mature B cells and B cell malignancies [
101]. Polatuzumab vedotin (Pola) is an anti-CD79b mAb conjugated to MMAE via a protease-cleavable linker similar to the structure of anti-CD22 ADC, pinatuzumab vedotin (Pina). Phase I trials demonstrated that single-agent Pola at a recommended dose of 2.4 mg/kg was effective against NHL but not for CLL [
102]. Both pola and pina were often studied in combination with rituximab. The ROMULUS trial showed that irrespective of CD79b expression, R-Pola was associated with a 54% ORR (21% CR), and a median PFS of 5.6 months for DLBCL patients, which was comparable to those from R-Pina; but for FL patients, R-Pola was associated with a 70% ORR (45% CR), and a median PFS of 15.3 months, much more effective than R-Pina. R-Pola shared a similar profile of AEs with R-Pina, but less incidence of SAEs [
103]. Therefore, the overall risk-benefit ratio favored Pola for further investigation in B cell NHL.
In an ongoing randomized phase II trial (NCT02257567), Pola was added to the regimen of bendamustine plus rituximab (BR) or obinutuzumab (BO) for patients with R/R DLBCL or R/R FL ineligible for autologous stem cell transplantation (ASCT). The interim result showed that the addition of Pola significantly improve ORR (45% vs. 18%), CR (40% vs. 18%), median OS (12.4 vs. 4.7 months), and PFS (7.6 vs. 2.0 months) [
104]. For the R/R DLBCL patients in this randomized phase II trial, 40 patients received Pola-BR, and 40 patients were randomized to BR only arm. In the Pola-BR arm, 25 (63%) patients achieved a PR/CR, versus 25% in the BR arm. The DOR was also longer in the pola-BR arm. Pola has been approved by FDA in June 2019 for R/R DLBCL who have failed at least two prior therapy and are not eligible for ASCT (Table
1). Pola is infused at 1.8 mg/kg over 90 min in combination with BR for the first cycle. Subsequent infusions may be administered over 30 min if the previous infusion is tolerated. The Pola-BR regimen is given every 21 days for a total of 6 cycles. One phase I/II trial (NCT01992653) reported that Pola plus obinutuzumab, cyclophosphamide, doxorubicin, and prednisone (Pola-G-CHP) yielded a 91% ORR (81% CR) with manageable toxicity profile. Common SAEs were neutropenia (38%) and febrile neutropenia (33%) [
105]. Another phase I/II trial (NCT01992653) investigated the combination of Pola with rituximab-cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP). An encouraging response with 91% ORR (78% CR) was also achieved. Most common SAEs were neutropenia (27%) and febrile neutropenia (11%) [
106]. A multicenter, randomized, double-blind, placebo-controlled phase III trial (POLARIX, NCT03274492) is currently ongoing to compare Pola-R-CHP to rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) as the first-line treatment for patients with newly diagnosed DLBCL.