Can BiTE Molecules Make Off-the-Shelf Immuno-Oncology a Reality?

Shaji Kumar, MD

Although chimeric antigen receptor (CAR) T-cell therapies have vastly improved clinical outcomes in treating some hematological malignancies, they come with substantial challenges, including cost, treatment delays, and the possibility of triggering cytokine release syndrome (CRS) in vulnerable patients.

Now, a new class of molecules is emerging that may ultimately offer clinical benefits comparable to those of CAR T-cell therapies while reducing some of the negatives associated with them. Bispecific T-cell engager (BiTE) therapies link endogenous T cells to tumor-expressed antigens to activate the cytotoxic potential of a patient’s T cells to kill cancer cells (FIGURE 1¹). Moreover, they do it without the need for ex vivo genetic alteration or manipulation of the T cells

A recent review article in Cancer described blinatumomab (Blincyto), which is used to treat acute lymphoblastic leukemia and is currently the only FDA-approved BiTE therapy.1 “[I]n its presence, T cells can perform serial-target lysis, rapidly binding and killing many cells,” wrote investigators Hermann Einsele, MD, et al. “This mechanism of action is the hallmark of BiTE therapies and is observed in other BiTE molecules under development.”

Based on the number of BiTE molecules in development, blinatumomab’s success may be a sign of things to come. The 62nd American Society of Hematology Annual Meeting and Exposition (ASH 2020) featured a broad complement of abstracts exploring BiTE therapy in both multiple myeloma and lymphoma.

“What’s reassuring about BiTE is that now we know that T cells are capable of mounting a strong response,” Shaji Kumar, MD, professor of medicine and consultant in the Division of Hematology in the Department of Internal Medicine at the Mayo Clinic Cancer Center in Rochester, Minnesota, told Targeted Therapies in Oncology. “Of course, we need larger studies, but we now have proof of platform to go after specific targets to broaden our treatment options.”

What follows are updated findings from some key studies, as well as what might lie ahead for these drugs.

BiTEs in Multiple Myeloma

TNB-383B TNB-383B is a B-cell maturation antigen (BCMA) x CD3 BiTE molecule that incorporates a unique anti-CD3 moiety that preferentially activates effector T cells over regulatory T cells and uncouples cytokine release from antitumor activity, reported Kumar, a study coauthor. Investigators recently presented results from their ongoing phase 1 dose-escalation and -expansion first-in-human study of TNB-383B (NCT03933735) at ASH 2020.²

This trial included 38 heavily pretreated patients with relapsed/refractory multiple myeloma. Its primary objectives were to determine the safety and tolerability of TNB-383B as well as its clinical pharmacology. Investigators also sought to identify the maximum tolerated dose and recommended phase 2 dose.

Patients were treated with escalating doses of TNB-383B by IV every 3 weeks without step-up dosing. Participants had a median of 7 prior lines of therapy.

At lower doses of up to 1.8 mg (n=15), the ORR was 13%, with no CRs. The ORR increased to 52% at doses from 5.4 to 40 mg (n=23), with a CR rate of 13%. Of 4 patients evaluable for MRD, 3 were found to be negative.

The most common treatment-related AE was CRS, with a rate of 21%; all cases were grade 1 or 2. The median time to onset of CRS was less than 1 day (range, 0-7 days), and the median duration was 1 day (range, 1-7 days). Three patients were treated with tocilizumab.

Responses have been fairly durable, Kumar reported. “Notably, we’re seeing a higher response rate with higher doses and, even with limited follow-up, we have seen some patients have sustained responses of 9 months,” he said. “Once we reach the maximum tolerated dose, there will be an expansion. That will give us a better sense of toxicity and efficacy as well, but so far, our expectations have been borne out.”

Deepu Madduri, MD

AMG 701

AMG 701 is a half-life–extended BiTE molecule that binds BCMA on myeloma cells and CD3 on T cells in relapsed/refractory multiple myeloma. A first-in-human study (NCT03287908) evaluated safety and tolerability and sought to identify a recommended phase 2 dose.³

By July 2020, 75 heavily pretreated patients had received AMG 701. The objective response rate (ORR) was 36% at doses of 3 to 12 mg (16 of 45 patients). In earlier dose-escalation data (n= 6), there was an 83% ORR, with 4 of 5 responders having triple refractory disease. The median treatment duration was 6.1 weeks, and the median follow-up was 1.7 months.

In total, responses included 4 stringent complete responses (CRs), 1 CR in which the patient was minimal residual disease (MRD) negative, 6 very good partial responses (VGPRs), and 6 PRs (FIGURE 2). The median time to response was 1.0 month, and the median time to best response was 2.8 months. The median duration of response (DOR) was 3.8 months, with a maximum DOR of 23 months. The investigators reported that 14 of 17 patients had an ongoing response at their most recent assessment.

Patients received AMG 701 intravenous (IV) infusions weekly in 4-week cycles until disease progression. To reduce the risk of severe CRS, investigators added a 0.8-mg step-up dose before target doses of 1.2 mg or greater. The first cohorts received doses up to 1.2 mg. Patients in later cohorts (n= 3-10 each) received 1.6 to 18 mg of AMG 701.

CRS, the most common nonhematological adverse event (AE), was observed in 61% of patients. Five patients (7%) had grade 3 CRS. These cases were all reversible with corticosteroids and tocilizumab (Actemra), and the median duration was 2 days.

Deepu Madduri, MD, assistant professor, Department of Medicine, and assistant professor, Department of Urology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, is an AMG 701 coauthor. “AMG 701 is currently on an FDA clinical hold, but we believe this molecule shows encouraging activity and a manageable safety profile that supports further evaluation,” she said in an interview with Targeted Therapies in Oncology. Regarding the pause, Amgen stated in a press release that the phase 1 study was paused as it discussed “protocol modifications to optimize safety monitoring and mitigation with the FDA.”⁴

Talquetamab (JNJ-65507564)

Talquetamab (JNJ-65507564) BCMA is not the only potential target of BiTEs. Talquetamab binds to CD3 and GPRC5D, an orphan receptor that is highly expressed in primary multiple myeloma cell culture but has only limited expression elsewhere. Investigators presented initial results from the ongoing, first-in-human, phase 1 dose-escalation study of talquetamab (NCT03399799) at ASH 2020.⁵

Notably, this trial includes both an IV and a subcutaneous cohortg. Investigators identified a recommended phase 2 dose of 405 µg/ kg given subcutaneously. At this dose, the ORR was 69% (9 of 13 patients), 39% of whom achieved a VGPR or better. Among responders, the median follow-up was 3.7 months (range, 1.7-6.5 months). The median time to first response was 1 month. Two-thirds (6 of 9) of patients with triple-refractory disease responded, as did both patients with pentarefractory disease.

Nearly half of all patients developed CRS (47%), with most cases being grade 1 or 2. However, 5 patients in the IV cohort developed grade 3 CRS. Patients typically developed CRS in their first cycle, with a median time to onset of 1 day (range, 1-3 days) for IV and 2 days (range, 1-5 days) for subcutaneous dosing.

“Investigators did see some neurotoxicities and cutaneous reactions, which were to be expected due to surface antigen involvement,” Kumar said. “Importantly, subcutaneous administration is more comfortable for patients and easier for institutions to manage. This would open up an important new treatment option for our patients, especially the elderly or frail ones.”

BiTEs in Lymphomas

IGM-2323 The use of BiTE molecules in lymphomas appears to show promise comparable to that seen in multiple myeloma. One such molecule is IGM-2323, a novel type of bispecific antibody that binds to CD20 and CD3. Investigators presented preliminary results from the first-in-human, phase 1 dose-escalation study (NCT04082936) at ASH 2020.⁶

Focusing on adults with relapsed/refractory B-cell non-Hodgkin lymphoma, this trial was designed to evaluate the safety, tolerability, and preliminary antitumor activity of IGM-2323. As of the data cutoff date for the ASH presentation, 8 patients had been treated by June 12, 2020.

Of the 14 patients treated in the 0.5-, 2.5-, 10-, 30-, and 50/100-mg dose cohorts, 9 saw their tumors shrink. Two patients achieved PRs, including a patient with follicular lymphoma (50/100-mg dose level) and another with diffuse large B-cell lymphoma (30-mg dose level) for whom CAR T-cell therapy had previously failed. Following data cutoff, the 2 patients with follicular lymphoma treated at the 50/100-mg titration dose converted to CRs, lead author Elizabeth Budde, MD, PhD, of City of Hope Comprehensive Cancer Center in Duarte, California, said at the conference.

Among all patients, IGM-2323 was found to be generally well tolerated, with no doselimiting toxicities, no grade 3 or higher CRS, and no evidence of neurotoxicity observed, Budde told colleagues.

“Preliminary results from this first-inhuman T-cell–engaging antibody study show an improved safety and tolerability profile at higher doses,” Budde said. She noted that there is also evidence of a novel mechanism of action based on T-cell activation and preservation of T-cell function compared with other T-cell engaging antibodies.”

AFM13 AFM13 targets CD30 on tumor cells and CD16A on natural killer (NK) cells and macrophages. Investigators presented the updated results of a phase 1b/2a study of patients with CD30-expressing lymphoma with cutaneous involvement (NCT03192202) at ASH 2020.⁷

AFM13 monotherapy produced an ORR of 43% in 6 of 14 patients. It also demonstrated clinical activity after brentuximab vedotin (Adcetris) failure in 2 of 4 patients. Tumor biopsies of responders showed increased pretherapy CD56-positive NK cell infiltration compared with nonresponders. Responders’ tumors also expressed granzyme B, indicating NK cell cytotoxicity.

“Together, these data suggest that AFM13 may initiate NK cell tumor infiltration and recruit and engage NK cells,” lead author Ahmed Sawas, MD, of Columbia University Vagelos College of Physicians and Surgeons and NewYork-Presbyterian Hospital in New York, New York, said during his presentation.

Investigators recruited 4 cohorts of patients. Cohorts 1, 2, and 3 included 3 patients, and cohort 4 included 6 patients. Patients had received a median of 4 prior therapies. AFM13 dosing was as follows: 1.5 mg/kg IV weekly, 7 mg/kg IV weekly, 7 mg/kg continuous IV infusion over 5 days weekly, and 200 mg IV weekly. Patients received 8 weeks of therapy for up to 2 cycles. Patients also underwent regular skin biopsies.

“With AFM13, biological changes in NK infiltration and activation in the peripheral blood and tissue biopsy correlated with response,” Sawas said. The data suggest that innate cell engagers modulate NK and T-cell populations in the peripheral blood and tumor from patients, Sawas said.

Mosunetuzumab

Mosunetuzumab, a fully humanized immunoglobulin G1 CD20/CD3 bispecific antibody, is being studied in GO29781 (NCT02500407), an ongoing phase 1/1b dose-escalation and -expansion study. Updated results from the trial, which is evaluating the safety, efficacy, and pharmacokinetics of mosunetuzumab in patients with relapsed/refractory B-cell lymphoma, were presented at ASH 2020.

Authors led by Sarit E. Assouline, MD, MSc, Sir Mortimer B. Davis-Jewish General Hospital in Montreal, Quebec, Canada, presented data from group B. These patients received IV mosunetuzumab monotherapy as step-up doses. Patients who achieved a CR received mosunetuzumab in subsequent 21-day cycles for 8 cycles. Patients who had either a PR or stable disease received up to 17 cycles.

The trial enrolled 62 patients with follicular lymphoma who had received at least 2 prior therapies. The ORR was 68% (n = 42), with half the patients (n= 31) achieving a CR and 11 patients (18%) with a PR.

Patients in high-risk groups obtained impressive responses. Patients with doublerefractory disease had a 55% CR rate. Those with PI3K inhibitor–refractory disease (n=13) had an ORR of 92%, including an 85% CR rate. All 4 patients who had previously received CAR T-cell therapy responded to mosunetuzumab; 2 of them achieved a CR.

Responses appeared durable; with a median on-study time of 14.4 months, 26 patients remained in remission as of data cutoff, including nearly three-quarters of those who had achieved a CR. Among all 42 responders, the median DOR was 20.4 months (95% CI, 11.7 months-not reached). The median progression-free survival was 11.8 months (95% CI, 7.3-21.9 months).

Investigators also found the safety profile of mosunetuzumab to be acceptable. Although low-grade CRS was common, no patients developed grade 3 CRS.

What Is Ahead for BiTEs? Madduri sees a great deal of potential in the emerging class of BiTE therapies. “I expect we will be able to give BiTE therapies right off the shelf. In studies now, most of us can get a patient screened, enrolled, and started on therapy within 2 weeks, which is a significant advantage over CAR T therapies,” Madduri said. “And due to the lack of severe CRS and neurotoxicities, these drugs will likely be safer for frail patients [who have] a lot of comorbidities or rapidly progressing disease.”

Given these early successes and major commitments by the manufacturers, both Kumar and Madduri expect BiTE therapies to earn FDA approval in the relatively near future. “I think we’ll have one approved as early as mid-2022, with others to follow late in that year,” Madduri said.

_References:

_{1. Einsele H, Borghaei H, Orlowski RZ, et al. The BiTE (bispecific T-cell engager) platform: development and future potential of a targeted immuno-oncology therapy across tumor types. Cancer. 2020;126(14):3192-3201. doi:10.1002/cncr.32909}

_{2. Harrison SJ, Minnema MC, Lee HC, et al. A phase 1 first in human (FIH) study of AMG 701, an anti-B-cell maturation antigen (BCMA) half-life extended (HLE) BiTE (bispecific T-cell engager) molecule, in relapsed/refractory (RR) multiple myeloma (MM). Presented at: 62nd American Society of Hematology (ASH) Annual Meeting and Exposition; December 5-8, 2020; virtual. https://bit.ly/3sM5EZ1}

_{3. Rodriguez C, D'Souza A, Shah N, et al. Initial results of a phase I study of TNB-383B, a BCMA x CD3 bispecific T-cell redirecting antibody, in relapsed/refractory multiple myeloma. Presented at: 62nd ASH Annual Meeting and Exposition; December 5-8, 2020; virtual. https://bit.ly/35Wab1t}

_{4. Chari A, Berdeja JG, Oriol A, et al. A phase 1, first-in-human study of talquetamab, a G protein-coupled receptor family C group 5 member D (GPRC5D) x CD3 bispecific antibody, in patients with relapsed and/or refractory multiple myeloma (RRMM). Presented at: 62nd ASH Annual Meeting and Exposition; December 5-8, 2020; virtual. https://bit.ly/3qCTvE0}

_{5. Budde E, Gopal AK, Flinn IW, et al. Preliminary results of a phase 1 dose escalation study of the first-in-class IgM based bispecific antibody Igm-2323 (anti-CD20 x anti-CD3) in patients with advanced B-cell malignancies. Presented at: 62nd ASH Annual Meeting and Exposition; December 5-8, 2020; virtual. https://bit.ly/35YJPM4} 

_{6. Sawas A, Chen P-H Lipschitz M, et al. Clinical and biological evaluation of the novel CD30/CD16A tetravalent bispecific antibody (AFM13) in relapsed or refractory CD30-positive lymphoma with cutaneous presentation: a biomarker phase Ib/IIa study (NCT03192202). Presented at: 62nd ASH Annual Meeting and Exposition; December 5-8, 2020; virtual. https://bit.ly/39QYjiv}

_{7. Assouline SE, Kim WS, Sehn LH, et al. Mosunetuzumab shows promising efficacy in patients with multiply relapsed follicular lymphoma: updated clinical experience from a phase I dose-escalation trial. Presented at: 62nd ASH Annual Meeting and Exposition; December 5-8, 2020; virtual. https://bit.ly/395rQFT}