CLL Key Data-Readouts from ASH 2020

CLL Current Tx paradigm/Unmet need commentary

CLL treatment paradigm has seen a significant shift from chemoimmunotherapy to targeted therapies such a BTK inhibitors, PI3K inhibitors and the novel time- limited combinations. Ibrutinib is the current treatment of choice in front-line CLL, however, better safety profile over longer periods of time and more complete remissions remain an unmet need. Clinical development activity is focused on exploring new horizons for the next generation small molecule inhibitors with the intent to increase remission rates, depth of response and to have better safety profiles. Effective therapies for frail, high risk and heavily pre-treated relapsed/refractory patients are yet to be explored and established in specific patient populations

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Phase III SEQUOIA Trial

Context

CLL treatment paradigm has seen a significant shift from chemoimmunotherapy to targeted therapies such a BTK inhibitors, PI3K inhibitors and the novel time- limited combinations. Ibrutinib is the current treatment of choice in front-line CLL, however, better safety profile over longer periods of time and more complete remissions remain an unmet need. Clinical development activity is focused on exploring new horizons for the next generation small molecule inhibitors with the intent to increase remission rates, depth of response and to have better safety profiles. Effective therapies for frail, high risk and heavily pre-treated relapsed/refractory patients are yet to be explored and established in specific patient populations

Study Highlights

At mFU OF 18.2 months, efficacy and safety data of zanubrutinib in treatment naïve, del (17p) CLL patients (N= 97) is as follows:

Efficacy

  • ORR: 94.5%; CR: 3.7%; PR: 87.2%; PR with lymphocytosis: 3.7%
  • SD: 4.6%; PD: 0.9%
  • mPFS: NR; DoR: NR; OS: NR
  • Estimated 18-mo data – PFS: 88.6% (95% CI, 79.0-94.0); DoR: 84% (95% CI, 67.5-92.6); OS: 95.1% (95% CI, 88.4-97.9)

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%

Insights and Implications

The durable responses observed in high-risk TN patients after extended follow-up support the potential use of zanubrutinib in high-risk frontline CLL patients as an alternative to established BTKis, due to a better safety profile along with high ORR

Abstract #1307 #1318

BOVen and SEQUOIA TRIALS

Context

There is a growing interest in developing fixed/limited duration doublet/triplet treatment regimens driven by uMRD. The BOVen trial is evaluating one such triplet containing zanubrutinib (Brukinsa), Obinutuzumab (Gazyva) and venetoclax (Venclexta) for which results are presented below. Arm D in the SEQUOIA trial on the other hand is evaluating a combination treatment of zanubrutinib and venetoclax and using serial monitoring of uMRD to determine treatment discontinuation. This treatment arm began enrolling patients last year (2019) and the study is ongoing.

Study Highlights

At a mFU of 14+ months, efficacy (N=37) and safety (N=39) results for zanubrutinib, obinutuzumab and venetoclax combination in previously untreated CLL patients is as follows:

Efficacy

  • uMRD (PB): 92%; uMRD (BM): 84%; median time to BM uMRD: 6 mos
  • OR: 100%; CR/CRi: 49%
  • Prespecified MRD endpoint – ORR: 77%; CR/CRi: 55%; PR: 45%

Safety

  • Grade ≥3 AEs – neutropenia: 15%; thrombocytopenia: 5%; rash: 5%; pneumonia: 5%

Insights and Implications

  • Zanubrutinib is one of the second-generation BTKis being evaluated in triplet combination in MRD-guided treatment
  • Studies have been done for zanubrutinib in frontline 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 BTKis
  • 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 treatment for an indefinite time
  • Long-term follow-up of all the triplets will determine the duration of treatment-free remission and the choice of BTKi to incorporate into each regimen

Phase Ib CVAY736Y2102 Trial

Context

The BTKis are established SOC for CLL patients but long-term use leads to development of resistance and cumulative toxicity. VAY736 is a BAFF-R-targeting mAb that is being evaluated with ibrutinib with an intention to achieve deep responses in R/R CLL patients so they can eventually discontinue ibrutinib.

Study Highlights

Dose escalation data for VAY736 and ibrutinib combination, for patients (N=15) who were previously receiving ibrutinib is as follows:

Efficacy

  • Overall response – CR: 40%; SD: 27%; PD: 27%
  • 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: 27% – neutropenia: 21%; hypophosphatemia: 14%; decreased WBC count: 7%; leukocytosis: 7%; increased lymphocyte count: 7%; hypertension: 7%; hypokalemia: 7%; hypomagnesemia: 7%

Insights and Implications

  • VAY736 inhibits BAFF-R activity and antagonizes the alternative NF-κB signaling that ibrutinib is unable to antagonize leading to potential synergistic action of these two agents. BAFF signaling has been shown to be a driving factor in disease progression in CLL as BAFF-R engagement activates prosurvival activity in B cells via NF-κB-inducible kinase-mediated alternative NF-κB signaling.
  • Preliminary data analysis supports the use of lanalumab as promising add-on therapy to ibrutinib for R/R CLL patients to achieve deeper responses. The trial will also be assessing VAY736 + ibrutinib in patients who either failed to achieve a CR after >1 yr with ibrutinib or developed a mutation associated with resistance to ibrutinib; successful demonstration of efficacy in these patients will address a huge unmet need in this subgroup

Phase II CAPTIVATE Trial

Context

Ibrutinib and venetoclax are both established agents in CLL and synergistic antitumor activity has been previously observed with ibrutinib + venetoclax; the CAPTIVATE trial is evaluating whether a frontline, 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 whether this regimen allows for treatment-free remission is what needs to be determined.

Study Highlights

Primary results of ibrutinib and venetoclax combination in treatment naïve patients (N=63) is as follows:

Efficacy

  • uMRD (PB): 48%; uMRD (BM): 32%
  • 1-yr DFS rate in placebo vs. ibrutinib: 95.3% (95% CI, 82.7-98.8) vs. 100% (95% CI, 100-100)
  • Confirmed uMRD, ibrutinib (N=43) vs placebo (N=43), 30-mo PFS rate: 100.0 (95% CI, 100.0-100.0) vs 95.3 (95% CI,82.7-98.8)
  • Unconfirmed uMRD, ibrutinib (N=31) vs ibrutinib+ venetoclax (N=32), 30-mo PFS rate: 95.2 (95% CI, 70.7-99.3) vs 96.7 (95% CI, 78.6-99.5)

Safety

  • Grade 3/4 AEs – neutropenia: 36%; hypertension: 10%; thrombocytopenia: 5%; diarrhea: 5%

Insights and Implications

  • MRD-guided follow-on treatment in patients receiving ibrutinib + venetoclax in 1L CLL patients supports a fixed-duration regimen in those with confirmed uMRD and eliminates 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 yrs) and possibly lesser tolerant, the treatment-free remission with deep responses and a manageable safety profile conferred by fixed-dose ibrutinib + venetoclax should prove to be an excellent treatment choice

Executive Conclusion

With the introduction of novel agents treatment of CLL is being re-examined in the current era. Their better safety and efficacy profile are likely capable of replacing the current SOC. However, to decide upon this a very long follow up is required. This may significantly delay use of novel regimes for patients in need. As a result, MRD analysis is being looked upon as the most appropriate clinical trial endpoint to evaluate better treatment option for patients.

Phase II AVO Trial

Context

The 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. The trial is based on encouraging efficacy data obtained from a triplet combination of ibrutininb, venetoclax and obinutuzumab that suffered from the disadvantage of a high rate of infusion-related reactions and toxicities, primarily related to ibrutinib. To achieve a more tolerable safety profile while maintaining the benefits of the triplet regimen, ibrutinib was replaced with acalabrutinib.

Study Highlights

Updated efficacy (N=24) and safety (N=37) data at mFU of 16 months, evaluating acalabrutinib, venetoclax and obinutuzumab triplet combination in previously untreated, high risk CLL patients is as follows

Efficacy

  • ORR: 100%; CR/CRi: 43%; PR: 57%
  • uMRD (PB): 84%
  • uMRD (BM): 78%
  • High-risk patients – CR: 40%; PR: 60%; uMRD (PB): 90%; uMRD (BM): 70%

Safety

  • Grade 3/4 heme toxicities – neutropenia: 34%; thrombocytopenia: 23%; anemia: 4.5%; infusion-related reactions: 2%
  • Serious AEs – neutropenia (grade 4): 9%; lung infection (grade 3): 2%; cardiac troponin increase (grade 3): 2%; thrombocytopenia (grade 3): 2%; hyperkalemia (grade 3): 2%
  • Grade ≥3 AEs – headache: 2%; fatigue: 2%; hypocalcemia: 2%

Insights and Implications

  • The updated data confirm that the AVO triplet is highly effective as time-limited therapy to achieve deep responses and reliable uMRD in previously untreated CLL patients
  • The AVO triplet regimen appears to augment efficacy as is, by encouraging high response rate along with high uMRD when compared to the BTKi-BCL2i doublet (CAPTIVATE). This could be attributable to multiple factors, including the addition of anti-CD20 and the choice of BTKi leading to more durable and deeper responses
  • Successful approval of the limited-duration triplet combination in 1L CLL could be a game changer in the current treatment paradigm; however, as the risk of additive toxicity is likely to remain, identification of optimal treatment duration in practise will be the key

Executive Conclusion

Toxicities, inevitable resistance, and the growing cost of indefinite therapy have represented the need to investigate time limited combination therapy of targeted agents. Investigation of multiple combination targets to obstruct tumor growth is effective in inducing rapid undetectable MRD responses and long-term treatment goals. But would it be really effective in the long run if patients relapse to these agents

Context

The use of BTKis has been an effective strategy for treating CLL but conventional BTKis have been associated with severe AEs and the development of resistance. While second-generation BTKis 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 BTKi being developed to overcome the issues associated with earlier BTKis.

Study Highlights

A RP2D of 200mg QD was selected for the drug. Preliminary safety and efficacy (N=65) data of LOXO-305 at mFU of 3 months in R/R CLL patients, who have received >2 prior therapies are as follows:

Efficacy

  • ORR: 57%; PR: 35%; PR-Ls: 22%
  • SD: 40%; PD: 3%
  • At 6-mo mFU – ORR: 77%

Safety

  • TEAEs overall – fatigue: 16%; diarrhea: 15%

Insights and Implications

  • LOXO-305 demonstrated deep responses and promising efficacy in heavily pretreated CLL patients with an improved safety profile compared to established BTKis
  • Considering response rates were not influenced by factors like prior therapy or the presence of mutations, LOXO-305 holds significant potential in catering to those with a poor prognosis, such as multiple prior treatments (including BTKi-BCL2i) and mutations (e.g., BTK C481) which may lead to discontinuation of prior BTKis

Context

UNITY-CLL is evaluating a next-generation PI3Kδi (umbralisib) and a glycoengineered anti-CD20 antibody (ublituximab) (U2) in TN and R/R CLL patients. Although currently available PI3Kis (idelalisib, duvelisib) exhibit high response rates and PFSs their use is associated with frequent discontinuations due to high incidence of AEs. Umbralisib overcomes this disadvantage via its dual action on casein kinase-1-ε and PI3Kδ. It is being combined with ublituximab based on an earlier observation of superior efficacy of the combination of a PI3Ki (idelalisib) and an anti-CD20 agent (rituximab) in R/R CLL.

Study Highlights

Data from sub-group analysis comparing umbralisib+ ublituximab (N=210) vs obinutuzuzmab and chlorambucil (N=211) in treatment naïve (N=240) and R/R CLL (N=181) patients are as follows:

Efficacy

  • mPFS at mFU of 36.2 mos: 31.9 mos vs. 17.9 mos (HR, 0.546; 95% CI, 0.413-0.720; p<0.0001)
  • 24 mos PFS rate (estimated): 60.8% vs 40.4%
  • ORR: 83.3% (95% CI, 78.1-88.6) vs. 68.7% (95% CI, 62.2-75.2; p<0.001)
  • mPFS in TN patients: 38.5mos vs 26.1mos (HR, 95% CI; 0.482[0.316-0.736])
  • mPFS in R/R patients: 19.5 mos vs 12.9 mos (HR, 95% CI, 0.601[0.415-0.869])
  • ORR in R/R patients: 57% vs 25%

Safety

  • Grade 3/4 AEs – neutropenia (30.6% vs. 34.7%); thrombocytopenia (3.4% vs. 13.1%); diarrhea (12.1% vs 2.5%); infusion related reaction (1.9% vs 3.5%); elevated AST/ALTs (8.3% vs 2%); colitis (3.4% vs 0%) and pneumonitis (2.9% vs 0%)
  • AEs leading to treatment discontinuation: 16.5% vs. 7.6%

Insights and Implications

  • TG Therapeutics is set to file for approval in both TN and R/R CLL patients by the end of 2020 or early next year; with a BTD in place, U2 is expected to receive expedited approval
  • Owing to a better safety and tolerability profile compared to first-generation PI3Kis, U2 could find rapid traction, especially in R/R CLL patients
    Once-daily dosing is also likely to drive patient preference for this combination
Abstract #544 and #546

Context

TRANSCEND-CLL-004 is evaluating lisocabtagene maraleucel (liso-cel), a CD19 CART with a defined composition of CD8+ and CD4+ CAR T cells in heavily pretreated, high-risk patients (del17p/TP53 mutation) who do not have many efficacious and safe treatment regimen options. Since ibrutinib had previously demonstrated an improvement in response to CART treatment, one of the cohorts of the trial is also evaluating liso-cel in combination with ibrutinib.

Study Highlights

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

Efficacy

  • Liso-cel
    Overall patients (N=23), BOR: 82% (95% CI, 59.7-94.8); CR/CRi: 45%; PR/Npr: 36%; SD: 14%; PD: 4.5%; uMRD (PB): 75%; uMRD (BM):65%
    Patients refractory to BTKi & venetoclax (N=11), BOR: 80 (95% CI, 44.4-97.5); CR/Cri:60%; PR/Npr: 20%; SD: 20%; uMRD (PB): 78%; uMRD (BM): 67%
  • Liso-cel+ ibrutinib
    Overall patients (N=19) at ≥1month FU, OR:95%; CR/CRi: 47%; SD: 5%; uMRD (PB): 89%; uMRD (BM):79%
    RP2D (N=15), OR: 100%

Safety

  • Liso-cel
    Overall patients (N=23), grade 3-4 TEAEs, thrombocytopenia:70%; anemia: 78%; neutropenia: 57%; leukopenia: 43%; CRS (grd3): 9%
    Patients refractory to BTKi & venetoclax (N=11), grade 3-4 TEAEs: thrombocytopenia: 55%; anemia: 73%; neutropenia: 45%; leukopenia: 18%; CRS (grd3): 18%
  • Liso-cel+ ibrutinib
    Overall patients (N=19), grade 3-4 TEAEs, neutropenia: 89%; anemia: 47%; febrile neutropenia: 26%
    RP2D(N=15), grade 3-4 TEAEs, neutropenia: 93%; anemia: 40%; febrile neutropenia: 27%

Insights and Implications

Liso-cel induced rapid and durable responses in high-risk cytogenetic patients with relapsed disease, especially those who failed on both BTKi and venetoclax. It is capable of producing undetectable MRD irrespective of the number of previous lines of therapy and hence, might address unmet need in heavily pretreated patients.

Novel mechanisms being tried in CLL

Context

Research and analysis into molecular biology and signalling 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 BTKis.

Study Highlights

Research and analysis into molecular biology and signalling 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 BTKis.

Insights and 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
  • Like BCL2i, second-generation MDM2i, KRT-232 acts by inducing apoptosis in malignant cells; however, it targets the p53-driven apoptotic pathway that is independent of BCL2 inhibition. In recent studies, a combination of BTKis and a BCL2i gave significant improvement in clinical efficacy; this indicates MDM2 as a promising target
  • A combination of these novel agents with established BTKis underpins the sustained use of BTKis in the long run in the treatment of CLL

Executive Conclusion

BTK, BCL2 and PI3K inhibitors have an established role in CLL treatment paradigm. Regardless of their profound results, there is an unmet need in patients relapsed/refractory to these regimens. To address these, novel regimens like MDM2 inhibitor, ROR1 inhibitor, CARTs and other higher generation BTK inhibitors are being developed. To foresee their adoption among patients, long term results or MRD negativity results are yet to be determined.

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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