ASH 2020 Highlights – Diffuse Large B Cell Lymphoma (DLBCL)
Prescient looks at the critical data presented at the American Society of Hematology (ASH) Annual Meeting and how they might affect the treatment paradigm in DLBCL.
- December 2020
Prescient Analytics
Jyotsana Chaudhary, MSc, Therapeutic Area Group Manager; Manisha Chugh, PhD, Senior Research Manager; Saugata Roy, MSc, Associate Research Manager; and Yashleen Kaur, MBA, Research Analyst
INTRODUCTION
Diffuse large B‐cell lymphoma (DLBCL) is the most common type of aggressive non‐Hodgkin lymphoma (NHL). Currently, R‐CHOP remains the backbone therapy for previously untreated DLBCL patients with 60% achieving durable remission. 40% of those who relapse or progress while on the frontline treatment may be treated with autologous stem cell transplantation (ASCT) or approved CD19-directed CARTs based on their eligibility to withstand such aggressive therapies. For patients who do not meet the criteria for such aggressive treatment, various options are now available based on recent approvals of agents like XPO1 inhibitor, selinexor (Xpovio), anti-CD79b ADC, polatuzumab vedotin (Polivy) and CD19-directed mAb, tafasitamab (Monjuvi). The approval of these novel therapies has come with new challenges such as optimal sequencing. One main challenge that remains is that most development in DLBCL is focused on treatment of relapsed/refractory (R/R) patients, while there is still a substantial proportion that has sub-optimal responses to the R-CHOP regimen.
ABSTRACT #1184
Bispecific Antibodies in DLBCL: Phase Ib/II GO40515 Study
Context
Although R-CHOP is a well- established treatment regimen for frontline DLBCL patients; 30-40% of patients progress while still on frontline treatment. There is an unmet need for effective therapies to delay progression and prevent early relapses.
Mosunetuzumab is a novel CD20/CD3 bispecific antibody that has shown promising safety and efficacy in R/R DLBCL patients. It is now being evaluated in combination with CHOP (M-CHOP) for its potential to reduce relapse rates in treatment-naive DLBCL patients and improve efficacy R/R in NHL patients.
Study Highlights
The study results in 1L and 2L+ patient segments are as follows:
Efficacy
- Newly diagnosed DLBCL (n=34) – ORR: 82.4%; CR: 79.4%; PR: 2.94%; PD: 8.8%
- R/R NHL (n=7) – ORR: 86%; CR: 85.7%; PD: 14.2%
Safety
- Newly diagnosed DLBCL (n=40) – Grade ≥3 AEs: 60%; SAEs: 30%; discontinuations: 7.5%; Grade 5 AEs: 2.5%; neutropenia (Grade 3): 2.5%; neutropenia (Grade 4): 62.5%; febrile neutropenia (Grade 3): 20%
- R/R NHL (n=7) – SAEs: 42.8%; Grade≥3 AEs: 57.1%; Grade 5 AEs: 14.3%; neutropenia (Grade 4): 29%; febrile neutropenia (Grade 3): 14.3%
- Newly diagnosed DLBCL (n=40)
Insights and Implications
- Considering that >50% of newly diagnosed DLBCL patients are aged above 65 years and may experience suboptimal outcomes with the standard CHOP/chemotherapy regimen, there is an unmet medical need for treatment of frontline elderly/unfit patient population in DLBCL
- With high response rates in both frontline DLBCL and R/R NHL patients, M-CHOP paves the way for bispecific combination strategies as backbone chemotherapy regimens
Context
DLBCL patients that relapse on the frontline treatment usually have poor prognosis and chemo-sensitive R/R DLBCL patients usually are treated with autologous hematopoietic stem cell transplantation (auto-HCT) consolidation as the SoC but the outcomes are still poor in this population, with only 40% achieving a PFS of 5 years. Blinatumomab, a first-in-class CD3/CD19 bispecific T-cell engager, is being evaluated as a post-auto-HCT consolidation therapy for its potential to reduce the relapse and increase the survival rates in R/R patients.
Study Highlights
The results of the study of blinatumomab as consolidation therapy post auto-HCT for DLBCL patients (N=10) are as follows:
Efficacy (N=10)
- CR (follow-up of 100 days after auto-HCT): 100%
- At median follow-up of 14.5 months, patients in remission: 60%
- OS: 100%
- PFS: 60%
- MRD-negative patients (Day 42): 80%; MRD-negative patients (Day 100): 100%
Safety
- No Grade 3-4 CRS and neurotoxicity; transient tremor (Grade 3) (10%)
Insights and Implications
Blinatumomab has already demonstrated long-term safety and has the potential to induce sustained remission and survival benefit as salvage treatment in R/R DLBCL patients
Considering it was well tolerated and all treated patients developed MRD negativity at the time of assessment in this pilot study, blinatumomab has the potential to improve outcomes in R/R DLBCL patients undergoing auto-HSCT and establish itself in the R/R post-HSCT consolidation setting
Context
First in-class IgM-based CD20 x CD3 bispecific antibody, IGM-2323, is claimed to bind with greater avidity to CD20-expressing cancer cells compared to an IgG bispecific. This ability may prove advantageous in binding to cancer cells that express lower amounts of CD20 on their surfaces. Clinically, it will have scope to act in patients in whom CD20 expression has been reduced due to prior treatment with another anti-CD20 antibody, such as rituximab. It is currently being evaluated in R/R NHL patients who have failed at least two prior systemic therapies.
Study Highlights
Preliminary safety results for IGM-2323 in 3L+ R/R DLBCL patients are as follows:
Safety
- n=8; no DLTs, no Grade-3 CRS and neurotoxicity observed; TEAEs: ≥20%
Insights and Implications
- IGM-2323 is designed to bind strongly to specific targets and has been preclinically shown to have a lower cytokine release profile compared to an IgG-based CD20 x CD3 antibody. If successfully applied in a clinical setting, IGM-2323 would have a significant advantage due to reduced occurrence of CRS with it
CAR-T Cell therapies in DLBCL
Context
Axicabtagene ciloleucel (Axi-cel, Yescarta) and tisagenlecleucel (tisa-cel, Kymriah) are the only two CARTs currently approved for the treatment of R/R DLBCL patients who have received at least two prior lines of therapy. Updated long-term follow-up data from the registrational ZUMA-1 (axi-cel) and JULIET (tisa-cel) trials will be presented. For tisa-cel, subgroup analysis has also been reported based on Myc overexpression, tumor microenvironment (TME) characteristics (including CD3+ T-cell infiltration) and LAG3 overexpression.
Study Highlights
Efficacy and safety data for axi-cel and tisa-cel are as follows:
Efficacy
Axi-cel (abstract #1187) – at median follow-up (mFU) of >4 years; n=101
- mOS: 25.8 months; 4-year OS rate: 44%
- 4-year follow-up; n=111; mOS (all patients): 17.4 months; 4-year OS rate (all patients): 41%
Tisa-cel (abstract #1194)- at median follow-up (mFU) of 40.3 months; n=115
- mOS: 11.1 months (95% CI, 6.6-23.9)
- PFS rate at 24 months: 33%; PFS rate 36 months: 31%
- Subgroup analysis data by Myc status and frequency of tumor infiltrating CD3+ T cells in table below
Insights and Implications
The long-term follow-up data reinforce the efficacy reported earlier and demonstrate that both CD19-directed CARTs can induce durable remission in treated patients
Considering that at two-year follow-up, patients showed evidence of persistence of axi-cel CAR T cells, the clearing up of functional CAR T cells at longer follow-up indicates that persistence of CAR T cells which is important to ensure antitumor immune response is not essential for long-term disease control
Subgroup analysis of tisa-cel in the JULIET trial further validates the prognostic value of Myc overexpression and an immunosuppressive TME in predicting poor treatment outcomes
The long-term follow-up data reinforce the safety and efficacy of both CARTs in R/R DLBCL patients, who now have more treatment options based on recent drug approvals. Both CARTs are now facing increasing competition from newly approved drugs that are available off the shelf and do not require a long and complex manufacturing process while providing comparable efficacy to CARTs
Context
R/R DLBCL patients usually have a poor prognosis. Their response rates and time to disease progression reduce with every relapse. Loncastuximab tesirine (lonca) is a novel anti-CD19 pyrrolobenzodiazepine-based antibody drug conjugate (ADC) that has shown good response rates in R/R DLBCL patients who had failed at least prior therapies. Updated data analysis of lonca is now being presented.
Study Highlights
Updated efficacy (n=145) and safety (n=145) data from the trial along with analysis of response in high-risk DLBCL patients are as follows:
Efficacy (follow-up ≥10 months)
- ORR: 48.3%; CR: 24.8%; PR: 23.4%
- mDoR: 12.58 months; mDoR for CR patients: 13.4 months; mDoR for PR patients: 5.68 months
- mPFS: 5.09 months
- mOS: 9.53 months
- ORR – double/triple hit: 33.3%
- ORR for patients refractory to 1L/recent/any prior therapy: 37.9%/ 36.9%/36.0%
- ORR for patients relapsed to 1L/recent/any prior therapy: 53.5%/67.4%/52.2%
- ORR for patients with prior CART therapy: 46.2%
- ORR for patients prior 2L/3L/3L+: 47.6%/48.6%/48.9%
Safety
- Grade ≥3 TEAEs: 72.4%
- Grade ≥3 TEAEs – neutropenia: 26.2%; thrombocytopenia: 17.9%; GGT increase: 17.2%; anemia: 10.3%
- TEAEs leading to discontinuation: 17.9%
Insights and Implications
CARTs are positioned to treat heavily pre-treated R/R DLBCL patients. Patients who relapse on CARTs have a poor prognosis and have no options left to treat the refractory disease. The success of lonca in inducing responses in CART-refractory patients makes it a potential option to fulfil the unmet need in this subgroup
Lonca could be the second ADC to be approved in DLBCL (PDUFA target date: May 21, 2021) after polatuzumab vedotin (Polivy). Unlike the approved ADC that is given in combination with chemotherapy, lonca provides the option of a chemotherapy-free regimen, especially for high-risk patients and transformed DLBCL patients, who achieved durable responses with single-agent lonca (mDoR: 13.4 months and NR, respectively)
CD20 x CD3 Bispecifics in DLBCL
Context
Recent advances in the development of therapies for DLBCL are dominated by emergence of newer modalities. Bispecific antibodies are one such class of products that are being increasingly evaluated to develop newer therapies for the treatment of both frontline and R/R DLBCL patients. Data are being presented for anti-CD20 x anti-CD3 bispecific antibodies odronextamab (REGN-1979), glofitamab (RG6026) and epcoritamab (GEN3013) that are being evaluated in R/R DLBCL patients and mosunetuzumab (RG7828) that is being evaluated in both newly diagnosed and R/R patient segments.
Study Highlights
Efficacy and safety results of bispecific mAbs that are being evaluated for frontline and R/R DLBCL patients are as follows:
Mosunetuzumab SC (R/R DLBCL, 2L+)
- Efficacy (n=36): ORR: 44.4% (aNHL); CR: 22.2% (aNHL)
- Safety (n=46): SAEs: 19.6 %; grade ≥3 AEs: 37%; grade 3/4 neutropenia: 30.4%; grade ≥3 CRS: 0%
Mosunetuzumab (Frontline, 1L)
At median follow-up of 5.4 months:
- Efficacy (n=22): Overall ORR: 63.5%; CR: 45.5%; PR: 18%
- Safety (n=29): SAEs: 14%; grade 3/4 AEs: 14%; grade 5 AEs: 0%; no grade 3 CRS; grade 3 neurotoxicity: 3%
Epcoritamab (R/R DLBCL, 2L+)
At median follow-up of 10 months:
- Efficacy
- At a dose of 12-60 mg (n=22): ORR: 68%; CR:46%
- At a dose of 48-60 mg (n=11): ORR: 91%; CR:55%
- Safety (n=68): SAEs: 68%; no grade 3/4 CRS; grade 3 TLS: 1.4%
Odronextamab (R/R DLBCL, 3L+)
- Efficacy
- Without prior CART (n=11): ORR: 55%; CR: 55%
- Post CART (n=24): ORR: 33%; CR: 21%
- Safety (n=136): SAEs: 44.9%; grade ≥3 AEs: 64%; grade 5 AEs: 3.7%; grade 3 CRS (overall): 6.6%
Glofitamab (R/R DLBCL, 2L+)
At median follow-up of 3.7 months:
- Efficacy (n=28): ORR: 60.7%; CR: 53.6%
- Safety (n=52): Grade 3/4 AEs: 29%; grade 3/4 TRAEs: 18%; grade ≥3 neutropenia: 21.2%; grade 4 CRS: 1.9%; AEs leading to treatment discontinuation: 2%
Insights & Implications
- Anti-CD20 x CD3 bispecific mAbs are set to have a significant impact on the treatment of DLBCL and other B-cell lymphomas with their CART-like T-cell engaging mechanism and clinical activity. Emerging bispecifics in DLBCL have shown encouraging efficacy signals and tolerable safety profiles across various trials
- Mosunetuzumab is being evaluated as both IV and SC formulations and as monotherapy. The SC formulation offers the advantages of ease of administration, greater patient compliance and reduction in the severity of CRS
- Regeneron’s odronextamab is likely to cater to a high unmet need – 3L+ DLBCL CART-refractory patients; the early Phase I dose-expansion study demonstrated encouraging preliminary data
- Step-up dosing like that presented for glofitamab (Roche) may provide for a CRS mitigation strategy and high-dose drug administration, prompting higher and durable responses
- The other CD20 x CD3 bispecific, epcoritamab, is being evaluated in a number of trials with the aim to become the treatment partner of choice with the established SoC drugs or regimen
- Bispecifics are efficacious, less-toxic chemotherapy-free regimens that are available off the shelf and require less time to manufacture compared to CAR T-cell therapies; they, therefore, hold a very high potential to bring about a paradigm shift in the R/R DLBCL treatment continuum
- Durable responses and reduced intensity of CRS in longer-term follow-ups will significantly drive the uptake of bispecifics
- Physician preference for bispecifics vs. other novel modalities, like ADCs or CARTs, in a real-world setting remains unclear and potentially reiterates the need for risk stratification based on patient prognosis, tolerability and prior therapies received
Context
Although R-CHOP is the established chemotherapy regimen for patients with newly diagnosed DLBCL, patients with high-risk characteristics usually have a lower probability of achieving long-term disease remission with it. Optimal therapy for this patient group has not yet been established and highlights an unmet need in frontline DLBCL treatment. Axicabtagene ciloleucel (Axi-cel), an anti-CD19 CAR-T, is approved for the treatment of adults with R/R DLBCL who have failed two or more prior therapies. It is now being evaluated as frontline treatment in a Phase II study, ZUMA-12, to test its potential to provide benefit to high-risk DLBCL patients.
Study Highlights
Interim efficacy, safety and PK results (N=15) at median follow-up ≥3 months from ZUMA-12 are as follows:
Efficacy
At median follow-up of 9.3 months (n=27)
- ORR: 85%; CR: 74%; PR: 11%; SD: 15%
- Patients converted from PR to CR: 15%; SD To CR: 4%
- mDOR: NR; mPFS: NR; mOS: NR
Safety
At median follow-up of 9.5 months (n=32)
- Grade ≥3 AEs: encephalopathy: 16%; increased ALT: 9%; neutropenia: 9%; CRS: 9%; NE: 25%
Insights and Implications
- ZUMA-12 is the first study evaluating CAR T-cell therapy as 1L therapy in high-risk DLBCL patients
- Encouraging clinical activity in a patient setting with a high unmet need is a significant leap in the development of CAR T-cell therapies; however, grade ≥3 CRS and neurotoxicity remain a challenge
- The established precedence of CARTs in R/R DLBCL is likely to generate interest in CAR T-cell therapies moving up the treatment ladder; however, it will be imperative to see long-term efficacy and safety data to assess if the risk of CART exposure upfront translates into better clinical outcomes
ABSTRACT #404
Bispecific CART in DLBCL – MB-CART2019.1
Context
With their targeted immunotherapeutic approach, CART therapies have revolutionized the treatment of heavily pre-treated patients in hematological malignancies. However, around 7-33% patients either fail to respond or relapse following an initial significant response to CART therapy. In most cases, relapse to CART therapy is attributed to loss of the target antigen. One of the ways to overcome antigen loss following CAR-T cell therapy is by targeting more than one antigen receptor; MB-CART2019.1, a bispecific CART, has been designed to target CD19- and CD20-expressing cells. It is being evaluated in R/R DLBCL (2L+) patients.
Study Highlights
Results for MB-CART2019.1 in adult patients with CD20+ and CD19+ R/R B-NHL at the recommended dose of 2.5 X106 kg (DL2) body weight are as follows:
Efficacy
- ORR (n=6): 100%; CR: 33%; PR: 67%
Safety
- No DLTs, neutropenia, grade ≥3 CRS and neurotoxicity
Insights and Implications
- Bispecific CARTs targeting dual antigens on malignant cells is a promising approach to prevent early treatment failures with single-antigen CAR T-cell therapies
- MB-CART2019.1 is a CAR T-cell therapy targeting CD19 and CD20 epitopes. Preliminary results suggest no CRS or Grade 3 toxicities, which demonstrates a promising risk-to-benefit ratio
- Based on encouraging preliminary efficacy and safety data, evaluation of MB-CART2019.1 at a dose of 2.5 x 106/kg body weight in higher-phase trials for patients with R/R aggressive B-NHL are in progress
Context
DLBCL patients who relapse after HSCT or who are not candidates for HSCT have poor outcomes with standard therapies and need novel therapies to improve their treatment outcomes. The combination of brentuximab vedotin (BV), lenalidomide and rituximab has been shown to be effective and well tolerated in R/R DLBCL patients based on the results of the 2005-046 study conducted in the past. A Phase III study has been undertaken to further evaluate the potential of this combination in heavily pretreated (3L+) DLBCL patients who are ineligible for HSCT or CART therapy.
Study Highlights
Details of the study to evaluate the efficacy of BV in combination with lenalidomide and rituximab vs. placebo for the treatment of R/R DLBCL subjects are as follows:
- Trial design: Phase III, randomized, double-blind, placebo-controlled, multicentric trial
- Patient segment: 3L+ DLBCL; ineligible for HSCT or CAR T-cell therapy
- N=400
- Primary endpoints: PFS in the ITT and CD30+ populations (stratification to be based on CD30 expression >1% vs. <1%)
- Enrollment ongoing globally (Approx. 185 sites)
Insights and Implications
- BV is recommended by the NCCN for use under certain circumstances for CD30+ disease. The Phase III registrational trial of Seagen’s CD30-targeting ADC in combination with lenalidomide and rituximab could pave the way for an emerging niche patient population, driving treatment choices
- The trial is likely to validate the use of CD30 expression as a biomarker predictive of response or for more targeted patient selection for personalized treatment
ADC in DLBCL- Loncastuximab Tesirine
Context
Around 40% of DLBCL patients fail to achieve long-term remission with frontline therapies and as they progress on more lines of therapy, the probability to achieve remission decreases even further. A recent approach being followed for development of therapies for heavily pre-treated patients is to combine agents with different mechanisms to achieve synergistic results. Based on preclinical synergy, loncastuximab tesirine (lonca), a novel ADC, was combined with ibrutinib, a BTKi inhibitor, and was evaluated for clinical efficacy in a Phase I/II study, LOTIS-3, in 3L+ R/R DLBCL patients who have failed at least two prior lines of therapies. Updated data from the study were presented. Additionally, a new Phase III study has been planned to evaluate lonca in combination with rituximab (lonca-R), a CD20-targeting antibody, in 2L+ R/R DLBCL; study design is discussed below.Around 40% of DLBCL patients fail to achieve long-term remission with frontline therapies and as they progress on more lines of therapy, the probability to achieve remission decreases even further. A recent approach being followed for development of therapies for heavily pre-treated patients is to combine agents with different mechanisms to achieve synergistic results. Based on preclinical synergy, loncastuximab tesirine (lonca), a novel ADC, was combined with ibrutinib, a BTKi inhibitor, and was evaluated for clinical efficacy in a Phase I/II study, LOTIS-3, in 3L+ R/R DLBCL patients who have failed at least two prior lines of therapies. Updated data from the study were presented. Additionally, a new Phase III study has been planned to evaluate lonca in combination with rituximab (lonca-R), a CD20-targeting antibody, in 2L+ R/R DLBCL; study design is discussed below.
Study Highlights
Interim results of the Phase I LOTIS-3 trial established the MTD; preliminary safety and efficacy data are as follows:
Efficacy (n=29)
- Overall DLBCL (n=29) — ORR: 58.6%; CR: 31.0%; PR: 27.6%
- Non-GCB DLBCL (n=24) — ORR: 66.7%; CR: 37.5%; PR: 29.2%
- GCB-DLBCL (n=6) — ORR: 20%; PR: 20%
Safety (n=37)
- Grade ≥3 TEAEs: 62.2% — Anemia: 10.8%; neutropenia: 10.8%; thrombocytopenia: 5.4%; fatigue: 5.4%
The design of the trial planned to evaluate lonca -R vs. R-GemOX is as follows:
- Study design: Phase III, randomized, open-label trial
- Estimated patient enrolment: Part 1: n=20, Part 2: n= 330
- Patient segment: 2L+ R/R DLBCL, double/triple hit
- Primary endpoint: PFS
- Secondary endpoints: OS, ORR, CR, DoR, AEs, PK and ADA
Insights and Implications
- With the PDUFA target date of May 21, 2021 (BLA based on LOTIS-2), lonca is all set to become the second ADC to be approved for the treatment of R/R DLBCL patients who have received two or more lines of therapy
- Promising clinical data from LOTIS-2 and encouraging interim efficacy and safety profile from LOTIS-3 demonstrate lonca’s potential to fulfil an existing unmet need for heavily pretreated patients who are predisposed to poor prognosis or intolerant or refractory to prior therapies
- The addition of lonca to the current SoC drugs will also explore the combination potential of ADCs with other regimens and facilitate expansion to earlier lines of therapy
Phase II GO29365 and Phase Ib/II GO29833 Trials of
Polatuzumab vedotin (Polivy)
Context
Polatuzumab vedotin (Polivy) (Pola) is a novel antibody drug conjugate (ADC) targeting CD79b on B-cells. It is approved in combination with bendamustine and rituximab (BR) for the treatment of 3L+ R/R DLBCL patients. The approval was based on the Phase II GO29365 trial which was later modified to include a single-arm Phase II extension (Ext) cohort of additional patients who received Pola + BR. Updated results from the GO29365 study, including the Phase Ib safety run-in cohort, Phase II randomized arms and previously unpublished results from the Ext cohort, are now being presented. Additionally, the potential of Pola is now being evaluated in early relapse (2L+) patients in combination with venetoclax (ven) and rituximab (R).
Study Highlights
Efficacy and safety data from Pola + BR vs. BR and Ext cohort of Pola + BR are as follows:
Pola + BR (n=40) vs. BR (n=40)
Efficacy (median follow-up of 42.9 months):
- mPFS: 9.2 months vs. 3.7 months; mOS: 12.4 months vs. 4.7 months; ORR: 42.5% vs. 17.5%
Ext cohort: Pola + BR (n=106)
Efficacy (median follow-up of 9.7 months)
- mPFS: 6.6 months; mOS: 12.5 months; ORR: 41.5%
Safety
Pola + BR (n=39) vs. BR (n=39)
- Grade 3-4 AEs: 87.2% vs. 71.8%; SAEs: 66.7% vs. 61.5%
Primary efficacy analysis results of Pola + ven + R in the Phase Ib/II GO29833 clinical trial are as follows:
Pola + ven + R
Efficacy (n=48): ORR (IRC): 29%; ORR (INV): 42%; mPFS: 4.4 months; mOS: 11.0 months
Safety (n=57): SAEs: 37%; grade 3-4 AEs: 79%; grade 3-4 AEs – neutropenia: 53%; infections: 16%; anemia: 11%; infections:16%
Insights and Implications
- Preliminary clinical data for the triplet (Pola + ven + R) in R/R DLBCL patients support the preclinical findings and warrants further evaluation
- Biomarker based efficacy analysis for Pola+Ven+R demonstrated higher CR in the del17p patients than the non del 17p; however, data in additional patients over long-term follow up will be needed to confirm these findings
- While Polatuzumab vedotin is approved in 3L+ R/R DLBCL, it is now being evaluated in combination with various agents in 2L+ to help it move up the treatment ladder. Approval of Pola in earlier treatment lines will help to establish it in a niche segment with better prognosis compared to CARTs that are also positioned in 3L+ settings
- Pola is the first ADC to be approved for R/R DLBCL (3L+) in combination with BR; the updated data from the registrational trial evaluating Pola + BR reinforce the potential of the combination to effectively treat R/R DLBCL. It may, however, face in-class competition from Polivy that is very close to approval and offers a chemotherapy-free regimen for R/R DLBCL patients
Context
Approval of CD19 CARTs has defined a new SoC in R/R DLBCL, but limited duration of response due to development of resistance with these agents remains an unmet need. Loss of CD19 antigens and CART cell exhaustion due to upregulation of PD‐L1 has been proposed to be a few of the mechanisms responsible for development of resistance to CD19 CARTs. One of the approaches to overcome the resistance based on this mechanism is to target more than one antigen receptor along with the use of a PDL-1 inhibitor. AUTO 3 has been developed to overcome the issue of resistance to CD19 CARTs caused by loss of CD19 or PDL1 upregulation; it is the first CD19/22-directed dual targeting CART that is being evaluated with pembrolizumab in the ALEXANDER trial for 2L+ R/R DLBCL.
Study Highlights
Efficacy and safety results of AUTO3, being evaluated in 2L+ R/R DLBCL, are as follows:
Efficacy
- Overall (n=43): ORR: 65%; CR: 51%
- Doses ≥ 300×106 (n=26): CR: 62%
- Doses ≥ 450×106 (n=15): CR: 73%
Safety
- Grade ≥3 AEs (n=49): Neutropenia: 57%; thrombocytopenia: 37%; anemia: 41%; CRS: 2%; neurotoxicity: 4%
Insights and Implications
- AUTO3 is one of the dual CAR-Ts that is being evaluated to overcome the resistance seen with the use of single agent targeting CD19 CAR-Ts. It showed a high rate of complete response along with a good safety profile
- Low-grade CRS and lack of severe neurotoxicity of any grade with AUTO3 make it feasible to be used in outpatient setting (the setting for the ALEXANDER trial) without the need for hospitalization
- With two anti-CD19 CARTs already established in DLBCL, it will be difficult for newer CARTs to find a niche for themselves; however, the lack of grade ≥3 CRS events, limited neurotoxicity, and the fact that in-patient setting is not mandatory for administration of AUTO3 will help pave way for greater adoption and utilization, especially in elderly frail patients who may not be otherwise considered fit to tolerate the AEs related to existing CARTs and cannot travel far to the specialized facilities to receive the therapy.
Novel Agents ALX-148, MG4101, Tebotelimab (MGD103),
KRT-232 and STRO-001
Context
The R/R DLBCL space has a high unmet medical need, with 40% of patients relapsing on frontline therapy. The treatment landscape of R/R DLBCL has recently witnessed many approvals and is booming with development of novel agents many of which are based on novel modalities. Some of the emerging novel agents are ALX-148 (anti-CD47 mAb), MG4101 (expanded allogenic NK cells), tebotelimab (MGD103, anti-PD1 x anti-LAG3 DART protein), KRT-232 (MDM2 inhibitor) and STRO-001 (CD74-targeting ADC).
Study Highlights
Efficacy and safety data presented for ALX-148, MG4101, MGD103, KRT-232 and STRO-001 in R/R DLBCL (2L+) patients are as follows:
ALX-148 is being evaluated in a Phase I study (ASPEN 01) as a single agent and in combination with rituximab in R/R DLBCL (2L+) patients.
Efficacy
- Dose 10 mg/kg (n=15)
- ORR: 33.3%; mDoR: 5.56%; mPFS: 2.53 months; mOS: 8.95 months
- Dose 15 mg/kg (n=5)
- ORR: 50%; DCR: 50%; mTTR: 1.88 months
Safety
- No DLTs; Grade ≥3 AEs: decreased neutrophil: 6.1%; anemia: 3%
MG4101 is being evaluated with rituximab in R/R DLBCL patients who have had one prior therapy (2L-7L).
- Efficacy (n=9): ORR: 55.6%; PR: 55.6%
- Safety (n=9): Grade 3 AEs: 77.8%; grade 3 neutropenia: 55.6%; no DLTs
Tebotelimab (MGD103) is being evaluated as a single agent in R/R DLBCL patients who are ineligible for SCT or have declined SCT
Efficacy
- Overall (n=13): ORR: 53.8%; CR: 15.4%; PR: 38.5%
- Prior CART (n=6): ORR: 33.3%; CR: 33.3%
- CART naïve (n=7): ORR: 71.4%; PR: 71.4%
Safety
- Grade ≥3 AEs: 45%; grade ≥3 SAEs: 20%; grade ≥3 anemia: 5%
KRT-232, is being evaluated in combination with acalabrutinib. Trial design is as follows:
- Phase Ib/II open label, multicentric trial
- Patient segment: R/R DLBCL, 2L+, BTK naïve with TP53 WT
- Estimated enrolment: Dose escalation (n=3-18); dose expansion (n=40)
- Primary endpoint — Phase Ib: RP2D; Phase II: CR rate
- Secondary endpoints: ORR, DoR, PFS and OS
STRO-001 is being evaluated as single agent for R/R NHL (n=21, including 7 DLBCL patients)
- Efficacy (DLBCL): 1 CR at a dose 0.075 mg/kg (n=1); 2 PR at a dose of 0.65, 1.27 mg/kg
- Safety: Grade 3 AEs — anemia (4.8%), dyspnea (4.8%); no ocular or neuropathy toxicity
Insights & Implications
- Through the CD47 blockade, ALX-148 bridges the innate and adaptive immune responses to NHLs and initial data presented are suggestive of encouraging responses with ALX-148 both as a single agent as well in combination with rituximab. The single agent and combination arms also demonstrated favorable hematologic safety profile; MTD was not reached
- With data from only 3 R/R DLBCL patients, none of whom reached a CR, it is too early to comment on the potential of MG1401 (expanded allogenic NK cells) in R/R DLBCL
- Both autologous and allogenic CARTs are associated with issues pertaining to manufacturing, logistics, toxicity and cost of treatment. Expanded allogenic NK cells are being developed to overcome several of these issues; however, they are still in early stages of development and sufficient safety and toxicity data need to be collected for them before they can become established and potentially overtake already approved CARTs in R/R DLBCL
- MGD013 is a bispecific DART protein designed to target both LAG3 and PD1, based on preclinical findings of synergy in targeting DLBCL cells. Preliminary response rates observed in CART-treated and CART-naïve patients warrant further investigation
- ADCs are an emerging treatment modality in DLBCL. Pola is the only approved ADC (closely followed by loncastuximab) for the treatment of R/R DLBCL patients. Like CARTs, ADCs display sufficiently high response and suffer from the disadvantages of causing CRS and neurotoxicity, but they offer the advantages of ease of administration, off-the-shelf availability and lack of a long and complex manufacturing process
The commentary included in this newsletter has been generated by the disease and market experts within Prescient’s dedicated Analytics function following analysis of publicly available sources of information.
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