ASH 2020 Highlights – Chronic Lymphocytic Leukemia (CLL)

ASH 2020 Highlights – Chronic Lymphocytic Leukemia (CLL)

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 CLL.

DECEMBER 2020

Prescient Analytics

Jyotsana Chaudhary, MSc, Therapeutic Area Group Manager; Manisha Chugh, PhD, Senior Research Manager; and Yashleen Kaur, MBA, Research Analyst

INTRODUCTION

Chronic lymphocytic leukemia (CLL) is a cancer of lymphocytes in the bone marrow. The CLL treatment paradigm has significantly evolved from chemoimmunotherapy (fludarabine-cyclophosphamide-rituximab (FCR)) to targeted therapies such as BTK inhibitors, BCL2 inhibitors and PI3K inhibitors which are recommended based on a patient’s functional status, comorbidities and cytogenetics (del(17p)/TP53). Ibrutinib is the current treatment of choice in front-line CLL; however, better safety profile over longer periods and more complete remissions remain an unmet need. At present, clinical development is focused on exploring new horizons for next-generation targeted therapies and novel time-limited combinations, with the intent to improve remission rates, depth of response and safety profiles. Nonetheless, effective therapies for frail, high-risk and heavily pre-treated relapsed/refractory (R/R) patients are yet to be explored and established.

Context

CLL patients with high-risk cytogenetics have poorer prognosis and develop rapid disease progression with suboptimal clinical activity of standard chemoimmunotherapy. Zanubrutinib (Brukinsa), a second-generation BTK inhibitor, has previously demonstrated a better safety profile compared to ibrutinib. Single-agent zanubrutinib is being evaluated in the open-label Phase III SEQUOIA trial as part of a non-randomized cohort (Arm C) for front-line (1L) high-risk CLL patients. These patients have poor prognosis due to del(17p) and impaired response to chemoimmunotherapy. Initial results were presented at a median follow-up of 10 months. Updated results with a longer follow-up are presented here.

Study Highlights

At a median follow-up of 21.9 months (5.0-30.2), efficacy and safety data of zanubrutinib in treatment-naïve, del(17p) CLL patients (n=109) who are ≥65 years of age or unsuitable for treatment with FCR are as follows:

Efficacy

  • ORR: 94.5%, CR: 5.5%; CRi: 0.9%; nPR: 0.9%; PR: 86.2%; PR with lymphocytosis: 0.9%
  • SD: 4.6%; PD: 0.9%
  • mPFS: NR; OS: NR
  • DoR≥ 12 months: 93.1%
  • Median time to progression: 13.6 months
  • 18-month PFS rate: 90.6%; DoR: 87.7%; OS: 95.4%
  • 18-month PFS in IGHV-mutated patients vs. unmutated patients: 94% vs. 88%
  • 18-month PFS in patients with complex karyotype vs. non- complex karyotype: 94% vs. 89%

Safety

  • Grade ≥3 AEs – neutropenia: 12.9%; pneumonia: 3.7%; bleeding: 5.5%
  • Other AEs – infections: 64.2%; bleeding: 47.7%; headache: 8.3%; hypertension: 8.3%; myalgia: 4.6%; skin tumors: 9.2%; non-skin secondary malignancies: 4.6%
  • Treatment discontinuations due to AEs: 4.6%; Grade 5 AEs: 1.8%
  • 2 deaths reported due to pneumonia and renal failure (in the context of PD); no sudden deaths reported

Insights & Implications

The durable responses observed in high-risk treatment- naïve patients after extended follow-up support the potential use of zanubrutinib in front-line (1L) high-risk CLL patients as an alternative to established BTK inhibitors, due to a better safety profile along with a high ORR

Despite the trial enrolling elderly patient population, ineligible for chemoimmunotherapy, safety profile was encouraging; Grade 3/4 pneumonia and bleeding were seen only in ~4-5% of patients, providing hope for the lesser-tolerant patient population

18-month PFS rates were similar in patients irrespective of their IGHV status and complex karyotype; the presence of unfavorable cytogenetics was not associated with inferior outcomes and supports zanubrutinib use in such patients

ABSTRACT #1307 #1318

BTK inhibitors-BCL2 inhibitor combinations: Phase II BOVen and Phase III SEQUOIA (Arm D)

Context

The approved combination of venetoclax (Venclexta) and obinutuzumab (Gazyva) demonstrates uMRD in ~50% of patients. While BCL2 and BTK inhibitors are considered synergistic, safety concerns with the ibrutinib combination remain; the more selective second-generation zanubrutinib combination with venetoclax and obinutuzumab is expected to achieve a higher uMRD. As there is a growing interest in developing fixed- and limited-duration doublet and triplet treatment regimens driven by uMRD, on the one hand, the BOVen trial is evaluating the triplet combination of zanubrutinib (Brukinsa), obinutuzumab (Gazyva) and venetoclax (Venclexta) in all patients irrespective of genetic cytogenetics. On the other hand, a treatment arm (Arm D) in another trial (SEQUOIA) is evaluating the combination of zanubrutinib and venetoclax in patients with del (17p) using serial monitoring of uMRD to determine treatment discontinuation. This treatment arm began enrolling patients in 2019 and is still recruiting.

Study Highlights

At a median follow-up of 15.2+ months, efficacy (n=37) and safety (n=39) results for the combination of zanubrutinib, obinutuzumab and venetoclax in previously untreated CLL patients are as follows:

Efficacy

  • uMRD (PB): 91.9%; uMRD (BM): 89.2%; median time to uMRD: 10 months (8 months of triplet)
  • OR: 100%; CR/CRi: 54.1%
  • Best uMRD (PB) (n=34): 100% (<104), 97.1% (<105), 14.7% (<106)
  • Confirmed uMRD (PB): 100% (<104), 86.7% (<105), 5.9% (<106)
  • Initial uMRD (BM) (n=33): 80.6% (<104), 38.7% (<105), 3.4% (<106)

Safety

  • Grade ≥3 TEAEs – neutropenia: 15.4%; thrombocytopenia: 5.1%; rash: 5.1%; infusion-related reaction: 2.6%

SEQUOIA (Arm D Study design) Highlights (Abs # 1318)

  • Trial design: Phase III, open-label, global, multicenter trial evaluating the combination of zanubrutinib and venetoclax in a non-randomized cohort (Arm D)
  • Patient segment: Treatment-naive del(17p) CLL (n=50)
  • Treatment regimen: Zanubrutinib, 160 mg 2QD for 3 months followed by the combination of zanubrutinib and venetoclax (ramp-up cycle followed by 400 mg QD) for 12-24 cycles until disease progression, unacceptable toxicity or requirements for uMRD at <10−4 sensitivity
  • Primary endpoint: PFS
  • Exploratory endpoints: OS, PROs and time to recurrence of detectable MRD after discontinuation of zanubrutinib and/or venetoclax
  • Secondary endpoints: ORR, PFS, DoR and rate of undetectable MRD at <104 sensitivity at different timepoints

Insights & Implications

  • Zanubrutinib is one of the second-generation BTK inhibitors being evaluated in a triplet combination in MRD-guided treatment
  • Studies have been conducted for zanubrutinib in front-line (1L) CLL patients; the data show that it has the potential to become a preferred combination partner, owing to its promising clinical activity and better safety profile than established BTK inhibitors
  • Triplet combinations such as zanubrutinib, obinutuzumab and venetoclax, which induce rapid and durable response and confirmed uMRD, have the potential to alter the CLL treatment landscape by providing patients with an option to remain in remission without continuing the medication for an indefinite time; BTK and BCL-2 inhibitor synergies are also being evaluated in high-risk patients
  • Long-term follow-up data will be required to optimally assess the MRD-driven treatment discontinuation strategy and determine the duration of treatment-free remission with the choice of BTK inhibitor in the combination regimen

Context

BTK inhibitors are the established SoC for CLL patients but their long-term use leads to development of resistance and cumulative toxicity. Ianalumab (VAY736) is a BAFF-R-targeting mAb that is being evaluated with ibrutinib (Imbruvica) with an intention to achieve deep responses in R/R CLL patients so they can eventually discontinue ibrutinib. BAFF signaling has been shown to be a driving factor in disease progression in CLL as BAFF-R engagement activates pro-survival activity in B cells via NF-κB-inducible kinase-mediated alternative NF-κB signaling.

Study Highlights

Dose escalation data for the ianalumab and ibrutinib combination in patients (n=15) who were previously receiving ibrutinib are as follows:

Efficacy

  • Overall response – CR: 40%; SD: 26.7%; PD: 26.7%
  • MRD negativity in patients who achieved CR: 20%
  • Median change in MRD (PB): -92.8%; median change in MRD (BM): -89.6%

Safety

  • Total Grade ≥3 AEs: 26.7% – neutropenia: 20%; decreased WBC count: 6.7%; increased lymphocyte count: 6.7%

Insights & Implications

Ianalumab inhibits BAFF-R activity and antagonizes the alternative NF-κB signaling that ibrutinib is unable to antagonize, leading to potential synergistic action with the combination
Preliminary activity supports the use of ianalumab as a promising add-on therapy to ibrutinib for R/R CLL patients to achieve deeper responses

The Phase Ib trial will also be assessing the combination of ianalumab and ibrutinib in patients who either failed to achieve a CR after >1 year with ibrutinib or developed a mutation associated with resistance to ibrutinib; successful demonstration of efficacy in these patients is likely to address the need for deeper responses and combat resistance, leading to clinical relapse in this subgroup

Context

Ibrutinib (Imbruvica) and venetoclax (Venclexta) are both established agents in CLL, and synergistic antitumor activity has been previously observed with their combination with the potential to achieve deep responses and time-bound treatment evaluations. The CAPTIVATE trial aims to evaluate whether a front-line (1L), chemotherapy-free, fixed-duration regimen can be developed with the combination that will achieve the desired MRD limit. High rates of uMRD were earlier reported from the trial but it needs to be determined whether this regimen allows for treatment-free remission.

Study Highlights

Primary results of the ibrutinib and venetoclax combination in treatment-naïve CLL patients (n=164) are as follows:

Efficacy

  • Best response of uMRD —
    • uMRD (PB, n evaluable=163): 75%;
    • uMRD (BM, n evaluable=155): 72%
  • In all treated patients (n=164), uMRD (PB): 75%; uMRD (BM): 68%
  • Confirmed vs. not confirmed uMRD with ibrutinib + venetoclax: 58% vs. 42%
    • Confirmed uMRD: 100% PB, 100% BM
    • Not confirmed uMRD: 48% PB, 32% BM
  • Patients with confirmed uMRD on 12 cycles of ibrutinib + venetoclax randomized to ibrutinib (continued treatment, n=43) vs. placebo (discontinued treatment, n=43)
    • 1-year DFS rate: 95.3% vs. 100% (p=0.1475)
  • Patients with not confirmed uMRD on 12 cycles of ibrutinib + venetoclax randomized to continued ibrutinib (n=31) vs. ibrutinib + venetoclax (n=32)
    • uMRD (PB): 45% vs. 69%
    • uMRD (BM): 42% vs. 66%

Safety

  • Grade 3/4 AEs – neutropenia: 36%; hypertension: 10%; thrombocytopenia: 5%; diarrhea: 5%
  • AEs leading to discontinuation in unconfirmed uMRD — ibrutinib vs. ibrutinib + venetoclax: 3% vs. 6%; no discontinuations due to AEs seen in confirmed uMRD patients post randomization

Insights & Implications

Comparable 1-year DFS rate between patients who discontinued ibrutinib-based regimen and those who continued active treatment (95.3% vs. 100%) after achieving uMRD post 12 cycles of ibrutinib + venetoclax in front-line (1L) CLL patients supports a fixed-duration treatment strategy
There is a need for additional and long-term follow-up data to confirm deeper MRD remissions and survival benefit. Successful clinical application of fixed-duration treatment approach will eliminate the need for continuous BTK inhibition for better outcomes and sustained hematological improvement

Considering the majority of CLL patients are elderly (median age of diagnosis: 65-70 years) and possibly lesser tolerant, treatment-free remission with deep responses and a manageable safety profile conferred by fixed-duration ibrutinib + venetoclax would make it an excellent treatment option for front-line CLL

Context

Although there are multiple targeted agents including anti-CD20, BCL2 inhibitors and BTK inhibitors with significant clinical efficacy, a proportion of CLL patients remain at a high risk of relapse and need specific, more selective treatment options. Although encouraging clinical activity was seen with the triplet combination of ibrutinib (Imbruvica), venetoclax (Venclexta) and obinutuzumab (Gazyva), patients reported a high rate of infusion-related reactions and toxicities, primarily related to ibrutinib. Replacing ibrutinib with acalabrutinib (Calquence) is hypothesized to be safer and active due to ibrutinib’s higher selectivity for BTK. The Phase II AVO trial is evaluating the time-limited triplet regimen of acalabrutinib, venetoclax and obinutuzumab with the expectation of achieving CR with high rates of uMRD.

Study Highlights

Updated efficacy (n=34) and safety (n=44) data at mFU of 16 months evaluating the triplet combination of acalabrutinib, venetoclax and obinutuzumab for front-line (1L) high-risk CLL patients are given below. Accrual in a TP53-aberrant cohort is ongoing.

Efficacy (Primary endpoint assessment is done at C16D1 for uMRD BM CR)

Response data at C16D1

  • Overall patient population (n=34): ORR: 100%; CR/CRi: 44%; PR/PR with lymphocytosis: 56%
  • TP53-aberrant population (n=10): ORR:100%; CR/CRi: 40%; PR/PR with lymphocytosis: 60%

MRD response data at C16D1, mFU: 19 cycles

  • Overall patient population: uMRD BM (n=34): 76.5%; uMRD PB (n=31): 83.9%
  • TP53-aberrant population: uMRD BM (n=10): 70.0%; uMRD PB (n=10): 90.0%

Safety (n=44)

Grade ≥3 AEs

  • Grade ≥3 AEs: Neutropenia (34%); thrombocytopenia (22%), anemia (5%), and hypocalcemia: 2%
  • Infusion-related reactions: 2%; Grade 3 lung infection: 2.3%
  • Serious AEs — Grade 4 neutropenia: 9%; Grade 4 hyperkalemia: 2%

    Insights & Implications

    There has been growing interest in evaluation of triplet combinations in CLL. The AVO triplet regimen in front-line CLL appears to augment efficacy by encouraging high response rates along with a high uMRD when compared to the CAPTIVATE doublet regimen of BTK and BCL2 inhibitors. This could be due to multiple factors, including the addition of anti-CD20 and choice of BTK inhibitor

    The updated data confirm that the AVO triplet regimen is promising as a time-limited frontline therapy to achieve deep responses and reliable uMRD in previously untreated CLL patients. Favorable toxicity profile (no TLS despite venetoclax ramp-up) further justifies its evaluation in larger trials

    • Patient accrual is ongoing in this Phase II trial for TP53-aberrant cohort and in a Phase III trial evaluating acalabrutinib + venetoclax + obinutuzumab vs. acalabrutinib + venetoclax vs. chemoimmunotherapy

    Successful approval of the limited-duration triplet combination in 1L CLL could be a significant advancement in the CLL treatment landscape; however, as the risk of additive toxicity is likely to remain, identification of optimal treatment duration will be the key

    Context

    The use of BTK inhibitors has been an effective strategy for treating CLL but conventional BTK inhibitors have been associated with severe AEs and development of resistance. Covalent BTK inhibitors such as ibrutinib (Imbruvica), acalabrutinib (Calquence) and zanubrutinib (Brukinsa) rely on the BTK cysteine binding site (C481) for their activity and mutations at these binding sites hamper their clinical activity. While second-generation BTK inhibitors offer a better safety profile, they have not been able to overcome common mechanisms of ibrutinib resistance. LOXO-305 is a novel selective and reversible non-covalent BTK inhibitor being developed to overcome the issues associated with earlier-generation BTK inhibitors.

    Study Highlights

    Safety and efficacy data of LOXO-305 in relapsed/refractory (R/R) CLL patients who have received >2 prior therapies are as follows:

    Efficacy (All patients, n=139)

    • ORR: 63%; CR:0%; PR:50%; PR-Ls:14%; SD: 32%
    • At follow-up ≥10 months (n=29), ORR: 86%

    Efficacy (BTK pretreated patients, n=121)

    • ORR: 62%; CR:0%; PR:47%; PR-Ls:15%; SD: 34%

    Safety (n=323)

    • TEAEs – Grade 3 hypertension: 1%; Grade 3 fatigue: 1%
    • TRAEs – Grade 3 fatigue in 2 patients (<1%)
    • No DLTs reported; MTD not reached
    • Treatment discontinuations due to AEs: 1.5%

    Insights & Implications

    • BRUIN, the first-in human Phase I/II study of LOXO-305, demonstrated deep responses and promising efficacy in heavily pretreated CLL patients with an impressive and improved safety profile compared to established BTK inhibitors
    • Encouraging efficacy data were seen regardless of prior BTKi exposure; longer follow-up will validate the initial findings
    • Considering the response rates were considerably higher irrespective of prior therapy or mutations, LOXO-305 holds a significant potential in catering to patients with poor prognosis and those developing resistance mutations (e.g., BTK C481) that lead to discontinuation of prior BTK inhibitors
    • Potential in earlier lines of therapy will be subject to comparisons with current SoCs including a direct comparison with the available covalent BTK inhibitors

    Context

    UNITY-CLL is evaluating a next-generation PI3Kδ inhibitor, umbralisib (TGR-1202), and a glycoengineered anti-CD20 antibody, ublituximab (TG-1101), in treatment-naïve (TN) and R/R CLL patients. Although currently available PI3K inhibitors (idelalisib and duvelisib) exhibit high response rates and PFS, their use is associated with frequent discontinuations due to a high incidence of AEs. Umbralisib overcomes this disadvantage via its dual action on casein kinase-1-ε and PI3Kδ. In addition, it is also being combined with ublituximab based on an earlier observation of superior efficacy of the combination of a PI3K inhibitor (idelalisib) and an anti-CD20 agent (rituximab) in R/R CLL.

    Study Highlights

    Data from the sub-group analysis comparing umbralisib + ublituximab (U2) (n=210) vs. obinutuzumab (O) and chlorambucil (Chl) (n=211) in TN (n=240) and R/R CLL (n=181) patients are as follows:

    Efficacy

    • ORR
      • Overall: 83.3% vs. 68.7% (p<0.001)
      • Treatment-naive: 84% vs. 78%
      • Relapsed/Refractory: 82% vs.57%
      • Relapsed/Refractory patients (prior BTK inhibitor exposure): 57% vs. 25%
    • mPFS: 31.9 months vs. 17.9 months (p<0.0001)
    • PFS events across Sub-groups
    • In TN patients: 30% (n=119) vs. 50% (n=121)
      • In R/R patients: 60% (n=91) vs. 70% (n=90)
      • In patients with del(17p): 68% (n=19) vs. 61% (n=23)
      • In patients with no del(17p): 41% (n=191) vs. 59% (n=188)
      • In patients with unmutated IGHV: 50% (n=113) vs. 70% (n=115)
      • In patients with mutated IGHV: 34% (n=50) vs. 36% (n=55)
      • U2 responses (n=210)
    • 62% patients maintained response at 2 years
      • DCR: 93%

    Safety

    • U2 (n= 206) vs. O + Chl (n=200), at median exposure of 21 months and 5 months, respectively
      • SAEs: 46.1% vs. 23.5%
      • Grade ≥3 AEs: 82% vs. 66%
      • Grade 5 AEs: 3.9% vs. 2.5%
      • Grade 3 AEs: Neutropenia (13% vs. 21%); thrombocytopenia (2% vs. 11%); diarrhea (12% vs. 3%)
      • Grade 4 AEs: Neutropenia (18% vs. 15%); thrombocytopenia (2% vs. 3%)
      • PI3K-specific grade ≥3 AEs: Elevated ALT (8.3% vs. 1%); elevated AST (5.3% vs. 2%); rash: (2.4% vs. 0.5%)
    • U2-specific grade 3-4 AEs
      • TN (n=116) – Neutropenia: 24.1%; diarrhea: 13.8%
      • R/R (n=90) – Neutropenia: 40%; diarrhea: 10%

    Insights & Implications

    • TG Therapeutics has initiated rolling submission on December 1, 2020 and expects to receive an expedited approval of U2 for TN and R/R CLL patients
    • Although response rates were similar in 1L and R/R settings, U2 is expected to show prolongation of PFS with longer follow-ups which may give way to positioning it as an available additional drug class, particularly in 1L
    • U2 may also be explored as a potential backbone combination partner in triplet combinations
    • Moreover, it might address an unmet need by offering a treatment option for candidates not eligible to take BTK and/or BCL2 inhibitors, given their toxicity profile and intolerability
    • Once-daily dosing is also likely to drive patient preference for this combination
    ABSTRACT #544 and #546

    Phase I/II TRANSCEND-CLL-004 Trial

    Context

    Novel agents such as ibrutinib (Imbruvica) or venetoclax (Venclexta) may achieve undetectable minimal residual disease (MRD) in patients; however, fixed-duration treatment or monotherapy with these drugs does not reliably keep patients MRD-negative for a long time. As eradication of MRD is necessary for achieving deep and durable responses in R/R CLL patients, lisocabtagene maraleucel (liso- cel) is being evaluated as a monotherapy and in combination with ibrutinib to achieve MRD-negative status; hence long-term durable responses in heavily pretreated high-risk patients is anticipated.

    Study Highlights

    Preliminary data of liso-cel as monotherapy and in combination with ibrutinib in 3L+ patient segment are given below:

    Liso-cel

    Efficacy
    At median follow-up of 24 months:

    Overall patients (n=23):

    • ORR: 82%; CR/CRi: 46%; PR/nPR: 36%
    • mDOR: NR; mPFS: 18 months

    Patients progressed on BTK inhibitors and failed venetoclax (n=11)

    • mDOR: 17 months; mPFS: 13 months

    Safety

    Overall patients (n=23), grade 3-4 TEAEs: Thrombocytopenia: 70%; anemia: 74%; neutropenia: 70%; leukopenia: 43%; NEs: 22%; CRS (grade 3): 9%
    Patients refractory to BTK inhibitors and venetoclax (n=11), grade 3-4 TEAEs: Thrombocytopenia: 55%; anemia: 64%; neutropenia: 73%; leukopenia: 18%; NEs: 27%; CRS (grade 3): 18%

    Liso-cel + ibrutinib

    Efficacy
    Overall patient population (n=19:

    • Best ORR: 95%; CR/CRi: 63% ; PR: 32%;
    • uMRD BM (≤ 10-4): 79%

    RP2D (DL2): 100 X106 CART cells
    Preliminary efficacy for high-risk patients at median follow-up of 10 months (n=15):

    • Best ORR: 100%; CR/CRi: 67%; PR: 33%; uMRD (≤ 10-4) (PB): 93%
    • uMRD (≤ 10-4) (BM): 80%

    Safety
    Safety data at the RP2D (n=15) for high-risk patients at median follow-up of 10 months

    
(Overall patient population vs RP2D)

    • Total grade 3-4 TEAEs: 95% vs. 93%
    • Neutropenia: 89% vs. 93%; anemia: 47% vs. 40%; febrile neutropenia: 26% vs. 27%
    • Grade 3 CRS: 5% vs. 0%; Grade 3 Neurologic events: 16% vs. 20%
    • Ibrutinib-related grade 3-4 TEAEs: 37% vs. 33%
    • Ibrutinib discontinuations due to TEAEs: 21% vs.20%

    Insights & Implications

    • Liso-cel in combination with ibrutinib induced rapid and durable responses in high-risk cytogenetic patients (~95% patients were high risk) with relapsed disease, especially those who failed on both BTK inhibitors and venetoclax
    • The combination has the potential to achieve high undetectable MRD rates irrespective of the number of previous lines of therapy and has better CRS profile (at RP2D in combination arm, no grade 3 CRS observed) indicative of potential to address an unmet need of deep responses in heavily pretreated patients
    Abstract #2942 and # 3024

    Data from Novel Targeted Agents explored in CLL (ROR1 and MDM2 inhibitor)

    Context

    Research and analysis into molecular biology and signaling pathways have led to the development and evaluation of novel therapeutic strategies to treat B-cell malignancies. The table below highlights two novel agents, one being evaluated and one planned for evaluation, in combination with first- or second-generation BTK inhibitors.

    Study Highlights

    Cirmtuzumab + ibrutinib
    Efficacy (data from Part 3 treatment schedule of the trial, treatment arms randomized 2:1)

    • Cirmtuzumab + ibrutinib vs. ibrutinib (n=15): best ORR: 93.3% vs. 100%; PR: 93.3% vs. 100%; SD: 6.7% vs. 0%

    Safety (n=71)

    • Grade ≥3 TEAEs: 57.7%
    • Neutropenia: 12.7%; thrombocytopenia: 1.4%; anemia: 2.8%

    KRT-232 (+ acalabrutinib): Trial design was presented for another novel targeted agent, KRT-232, being evaluated in TP53 wild-type BTK inhibitor-naïve and BTK inhibitor-intolerant CLL patients

    Insights & Implications

    • ROR1 is a tyrosine kinase receptor and unlike the established targets for anti-cancer agents, is expressed only by malignant cells, especially in CLL and MCL, which makes it a promising target for treatment that will have no or minimal effect on normal cells/biological function.
    • Cirmtuzumab in combination with ibrutinib is active in CLL, however it did not result in increased activity, the best response rates were lower than the ibrutinib alone arm (93 vs. 100%) in 2:1 randomization arms, Oncternal Therapeutics currently focuses development in MCL
    • Like BCL2i, second-generation MDM2i, KRT-232 acts by inducing apoptosis in malignant cells; it targets the p53-driven apoptotic pathway that is independent of BCL2 inhibition and provides a novel cell death mechanism
    • A combination of these novel agents with established BTKis underpins the sustained use of BTKis in the long run in the treatment of CLL.
    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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