A Review of Selected Presentations From the All-Virtual 62nd ASH Meeting and
Exposition • December 5-8, 2020
Umbralisib Plus Ublituximab Is Superior to Obinutuzumab Plus Chlorambucil in Patients With Treatment-Naive and Relapsed/Refractory Chronic Lymphocytic Leukemia: Results From the Phase 3 UNITY-CLL Study
The development of inhibitors of Bruton tyrosine kinase (BTK) and B-cell lymphoma 2 (BCL-2) has dramatically improved outcomes in both treatment-naive and previously treated patients with chronic lymphocytic leukemia (CLL).1 However, mechanisms of resistance to these agents have been identified. The mechanism of action of drugs that inhibit phosphoinositide 3-kinase delta (PI3Kδ) is distinct from that of BTK and BCL-2 inhibitors, and these drugs have yielded encouraging outcomes in patients with relapsed or refractory CLL.2,3 Despite promising efficacy, early PI3Kδ inhibitors were associated with high levels of toxicity, and discontinuation rates exceeded 50% in some studies. Umbralisib is a novel dual inhibitor of PI3Kδ and casein kinase 1ε that binds with greater selectivity to the δ isoform of PI3K than to other isoforms, with reduced rates of discontinuation owing to adverse events (AEs) and low rates of immune-mediated toxicities.4 The affinity of umbralisib for the δ isoform of PI3K is 1000-fold greater than its affinity for the α or β isoform, and its affinity for the δ isoform is 200-fold greater than its affinity for PI3Kγ. Ublituximab is a novel monoclonal antibody that targets CD20 and has been glycoengineered to increase antibody-dependent cellular cytotoxicity.5
The UNITY-CLL study evaluated umbralisib monotherapy, ublituximab monotherapy, the combination of umbralisib plus ublituximab (U2), and obinutuzumab plus chlorambucil for the treatment of CLL.6 Patients with treatment-naive or relapsed or refractory disease requiring treatment according to International Workshop on CLL (iwCLL) criteria were enrolled.7 They had adequate organ function and an Eastern Cooperative Oncology Group performance status of 2 or lower. Patients were stratified on the basis of chromosome 17 deletion (del[17p]) and prior treatment. Umbralisib (800 mg) was administered once daily until disease progression or cessation for other reasons. Ublituximab (900 mg) was administered as a split dose on days 1 and 2 of cycle 1 and then as a single dose on days 8 and 15 of cycle 1, on day 1 of cycles 2 through 6, and on day 1 of every third cycle after cycle 6. Obinutuzumab (1000 mg) was administered as a split dose on days 1 and 2 and then as a single dose on days 8 and 15 of cycle 1 and on day 1 of cycles 2 through 6. Chlorambucil (0.5 mg/kg) was administered once daily on days 1 and 15 of cycles 1 through 6. Each treatment cycle was 28 days. The primary endpoint was progression-free survival (PFS), assessed by an independent review committee. Secondary endpoints included the objective response rate (ORR), complete response (CR) rate, duration of response (DOR), undetectable minimal residual disease (MRD), and safety. Two interim analyses were planned. The first one, for futility only, was performed when 50% of independently assessed PFS events had occurred. The second, to evaluate the superiority of U2 vs obinutuzumab plus chlorambucil, was performed when 75% of those events had occurred. Enrollment into the umbralisib and ublituximab arms was discontinued after the data safety monitoring board determined that the contribution of each agent had been demonstrated.
The study enrolled 210 patients into the U2 arm and 211 patients into the obinutuzumab-plus-chlorambucil arm.6 In the U2 arm, patients had a median age of 67 years (range, 39-88), and 39% had Rai stage 3/4 disease. High-risk features included the unmutated immunoglobulin heavy chain variable (IGHV) region gene in 54%, del(11q) in 22%, and del(17p) in 9%. In the obinutuzumab-plus-chlorambucil arm, patients had a median age of 68 years (range, 36-91), and 35% had Rai stage 3/4 disease. High-risk features included unmutated IGHV in 55%, del(11q) in 18%, and del(17p) in 11%. In each arm, 57% of the patients were treatment-naive.
In the U2 arm, the median duration of drug exposure was 21.1 months (range, 0.03-46.3) for ublituximab and 20.5 months (range, 0.03-47.2) for umbralisib. In the comparator arm, the median duration of drug exposure was 4.7 months (range, 0.03-7.4) for obinutuzumab and 5.1 months (range, 0.03-7.4) for chlorambucil. The rate of treatment discontinuation owing to AEs was 17% in the U2 arm vs 8% in the comparator arm.
After a median follow-up of 36.2 months, the median PFS was 31.9 months in the U2 arm vs 17.9 months in the comparator arm (hazard ratio [HR], 0.546; 95% CI, 0.413-0.720; P<.0001; Figure 1). Among treatment-naive patients, the median PFS was 38.5 months vs 26.1 months, respectively (HR, 0.482; 95% CI, 0.316-0.736; P<.001). Among previously treated patients, the median PFS was 19.5 months in the U2 arm vs 12.9 months in the obinutuzumab-plus-chlorambucil arm (HR, 0.601; 95% CI, 0.415-0.869; P<.01). The ORR was 83.3% with the U2 regimen (5% CR rate) vs 68.7% (1% CR rate) with obinutuzumab plus chlorambucil (Figure 2).
Serious AEs were observed in 46.1% of patients in the U2 arm vs 23.5% of patients in the comparator arm. AEs of grade 3 or higher were observed in 82.0% of patients in the U2 arm vs 66.0% of patients in the comparator arm. Grade 5 AEs occurred in 3.9% vs 2.5% of patients, respectively. In the U2 arm, the most common grade 3/4 AEs were neutropenia (31.1%) and diarrhea (12.1%), followed by fatigue (1.9%) and infusion-related reactions (1.9%). The most common PI3K-related AEs of grade 3 or higher were alanine transaminase elevation (8.3%), opportunistic infections (5.8%), and aspartate transaminase elevation (5.3%).
References
1. Iskierka-Jażdżewska E, Robak T. Investigational treatments for chronic lymphocytic leukemia: a focus on phase 1 and 2 clinical trials. Expert Opin Investig Drugs. 2020;29(7):709-722.
2. Burris HA III, Flinn IW, Patel MR, et al. Umbralisib, a novel PI3Kδ and casein kinase-1ε inhibitor, in relapsed or refractory chronic lymphocytic leukaemia and lymphoma: an open-label, phase 1, dose-escalation, first-in-human study. Lancet Oncol. 2018;19(4):486-496.
3. Yosifov DY, Wolf C, Stilgenbauer S, Mertens D. From biology to therapy: the CLL success story. Hemasphere. 2019;3(2):e175.
4. Janovská P, Normant E, Miskin H, Bryja V. Targeting casein kinase 1 (CK1) in hematological cancers. Int J Mol Sci. 2020;21(23):E9026.
5. Babiker HM, Glode AE, Cooke LS, Mahadevan D. Ublituximab for the treatment of CD20 positive B-cell malignancies. Expert Opin Investig Drugs. 2018;27(4):407-412.
6. Gribben J, Jurczak W, Jacobs R, et al. Umbralisib plus ublituximab (U2) is superior to obinutuzumab plus chlorambucil (O+Chl) in patients with treatment naïve (TN) and relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): results from the phase 3 UNITY-CLL study [ASH abstract 543]. Blood. 2020;136(suppl 1).
7. Hallek M, Cheson BD, Catovsky D, et al; International Workshop on Chronic Lymphocytic Leukemia. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008;111(12):5446-5456.
Primary Analysis of ZUMA-5: A Phase 2 Study of Axicabtagene Ciloleucel in Patients With Relapsed/Refractory Indolent Non-Hodgkin Lymphoma
In patients with follicular lymphoma who have received 2 or more lines of treatment, CR rates with approved therapies are less than 15%, and the median DORs are 13 months or less.1-3 Axicabtagene ciloleucel is an autologous chimeric antigen receptor (CAR) T-cell therapy that binds to CD19. It is approved for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after 2 or more lines of systemic therapy.4 The single-arm, multicenter phase 2 ZUMA-5 trial evaluated axicabtagene ciloleucel in patients with relapsed or refractory follicular lymphoma or marginal zone lymphoma (MZL) who had previously received 2 or more systemic regimens.5 Key eligibility criteria included grade 1 to 3a follicular lymphoma or nodal or extranodal MZL and prior treatment with the combination of an anti-CD20 monoclonal antibody and an alkylating agent. The conditioning regimen consisted of fludarabine (30 mg/m2) plus cyclophosphamide (500 mg/m2), administered 5, 4, and 3 days before the axicabtagene ciloleucel infusion. The axicabtagene ciloleucel product was infused at a dose of 2 × 106 CAR T cells/kg. The study’s primary endpoint was the ORR, assessed by independent review according to the Lugano classification.6
The manufacture of axicabtagene ciloleucel was successful for the 151 patients enrolled in the trial.5 The drug was delivered to the study site at a median of 17 days after the patients had undergone leukapheresis. The infusion was administered to 124 patients with follicular lymphoma and 22 patients with MZL. The efficacy analysis included 104 patients, and the safety analysis included 146 patients. The median follow-up was 17.5 months for efficacy and 15.1 months for safety. At baseline, the patients had a median age of 61 years (range, 34-79), 86% had stage 3/4 disease, and 68% had refractory disease. The patients had received a median of 3 prior therapies (range, 1-10).
The independently assessed ORR was 92%, with a CR rate of 76%.5 The ORR in the patients with follicular lymphoma was 94%, with a CR rate of 80%. The ORR in the patients with MZL was 85%, with a CR rate of 60%. The ORRs with axicabtagene ciloleucel were consistent across key subgroups, such as those based on age and number of prior therapies. The median DOR was not reached, and the 12-month estimated DOR rate was 71.7% (95% CI, 60.7%-80.1%; Figure 3). Ongoing responses were more common among patients who had achieved a CR than in those with a partial response (PR; 78% vs 17%). The median PFS and median overall survival (OS) were not reached. The 12-month PFS rate was 73.7% (Figure 4), and the 12-month OS rate was 92.9%.
Among the 146 patients, the most common treatment-emergent AEs of any grade were pyrexia (84%), neutropenia (64%), and hypotension (49%).6 AEs of grade 3 or higher were reported in 126 patients (86%). The most common of these events consisted of cytopenias (70%) and infections (16%). Grade 5 AEs were reported in 3 patients (2%), including a case of multisystem organ failure, in the context of cytokine release syndrome, that was related to axicabtagene ciloleucel treatment. Cytokine release syndrome of at least grade 3 occurred in 10 patients (7%). Neurologic events of grade 3 or higher were reported in 19% of patients, with no grade 5 neurologic events. The median time to the peak level of engineered CAR T cells was 9 days (range, 8-371) after the axicabtagene ciloleucel infusion.
References
1. Dreyling M, Santoro A, Mollica L, et al. Phosphatidylinositol 3-kinase inhibition by copanlisib in relapsed or refractory indolent lymphoma. J Clin Oncol. 2017;35(35):3898-3905.
2. Flinn IW, Miller CB, Ardeshna KM, et al. DYNAMO: a phase II study of duvelisib (IPI-145) in patients with refractory indolent non-Hodgkin lymphoma. J Clin Oncol. 2019;37(11):912-922.
3. Gopal AK, Kahl BS, de Vos S, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370(11):1008-1018.
4. Yescarta [package insert]. Santa Monica, CA: Kite Pharma, Inc; 2020.
5. Jacobson CA, Chavez JC, Sehgal AR, et al. Primary analysis of ZUMA-5: a phase 2 study of axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory (R/R) indolent non-hodgkin lymphoma (iNHL) [ASH abstract 700]. Blood. 2020;136(suppl 1).
6. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059-3068.
A Phase 1/2 Study of Umbralisib, Ublituximab, and Venetoclax in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia
A multicenter phase 1/2 study evaluated the U2 regimen combined with venetoclax in patients with previously treated CLL.1 The goal was to reduce the risk for venetoclax resistance and tumor lysis syndrome, while increasing the eradication of malignant cells.2,3 The trial enrolled patients with CLL/small lymphocytic lymphoma (SLL) that had progressed after at least 1 prior regimen and required treatment. During the study, the protocol was amended to limit enrollment to patients who were unable to tolerate BTK inhibition or who had refractory disease. Patients with previous exposure to a PI3K inhibitor or a BCL-2 inhibitor were permitted to enroll. The dose escalation portion of the trial used a standard 3 + 3 design. During the phase 2 portion of the study, patients received 3 infusions of ublituximab (900 mg) during cycle 1, then a single infusion (900 mg) on day 1 of cycles 2 through 6. Umbralisib (800 mg) was administered daily. Venetoclax was initiated with cycle 4; the dose was ramped up to 400 mg in a standard 5-week schedule and was administered once daily through cycle 12. Each cycle was 28 days. The primary objective for phase 2 was the CR rate according to iwCLL criteria.4
For the safety analysis, 43 patients were evaluable, and 39 were evaluable for efficacy.1 Their median age was 64 years (range, 43-83). The median number of prior therapies was 2 (range, 1-6), and 33% had disease that was refractory to the most recent therapy. At least 1 high-risk feature was present in 79% of the patients, such as unmutated IGHV in 74%, del(11q) in 30%, NOTCH1 mutation in 27%, and del(17p) in 26%.
After 3 cycles of U2 therapy, the relative risk for tumor lysis syndrome was reduced by 81% (Figure 5).1 No cases of tumor lysis syndrome developed during the venetoclax ramp-up. After 12 treatment cycles, the ORR was 100% (59% CR rate/41% PR rate; Figure 6). MRD was undetectable in the peripheral blood in 96% of patients and in the bone marrow in 77%. After a median follow-up of 15.6 months, disease had progressed in only 1 patient. This patient had completed 12 cycles of therapy, with achievement of undetectable MRD in both the peripheral blood and bone marrow; disease progression was noted 10 months later.
The most common AEs of any grade included infusion reaction (60%), anemia (56%), thrombocytopenia (53%), and neutropenia (51%). Grade 3/4 AEs included neutropenia (21%), leukopenia (12%), infusion reaction (7%), anemia (5%), and diarrhea (5%). Grade 3/4 AEs of special interest included lung infection/pneumonia (7%), colitis (5%), tumor lysis syndrome (2%), and rash (2%). The umbralisib dose was reduced in 4% of patients. Umbralisib was discontinued in 9% of patients, and venetoclax was discontinued in 4% of patients. The ongoing phase 2 ULTRA-V study is evaluating U2 plus venetoclax in treatment-naive and previously treated patients.
References
1. Barr PM, Ma S, Zent CS, et al. A phase 1/2 study of umbralisib, ublituximab, and venetoclax (U2-ven) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) [ASH abstract 3137]. Blood. 2020;136(suppl 1).
2. Cervantes-Gomez F, Lamothe B, Woyach JA, et al. Pharmacological and protein profiling suggests venetoclax (ABT-199) as optimal partner with ibrutinib in chronic lymphocytic leukemia. Clin Cancer Res. 2015;21(16):3705-3715.
3. Choudhary GS, Al-Harbi S, Mazumder S, et al. MCL-1 and BCL-xL-dependent resistance to the BCL-2 inhibitor ABT-199 can be overcome by preventing PI3K/AKT/mTOR activation in lymphoid malignancies. Cell Death Dis. 2015;6(1):e1593.
4. Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131(25):2745-2760.
LOXO-305, A Next-Generation, Highly Selective, Non-Covalent BTK Inhibitor in Previously Treated CLL/SLL: Results From the Phase 1/2 BRUIN Study
Covalent BTK inhibitors have transformed the treatment landscape for CLL, but their use is limited by toxicities and the development of resistance.1-6 Mutation of the BTK gene (cysteine to serine substitution at the 481 residue) is the most common cause of CLL that progresses after treatment with a covalent BTK inhibitor. LOXO-305 is a selective, noncovalent inhibitor of BTK that has nanomolar potency against both wild-type BTK and BTKC481S in cell and enzyme assays.7,8 The phase 1/2 BRUIN study investigated LOXO-305 in patients with non-Hodgkin lymphoma (NHL). During phase 1, LOXO-305 was administered daily in doses ranging from 25 to 300 mg. Each cycle was 28 days. Intra-patient dose escalation was allowed, and cohort expansion was permitted at doses that were considered safe. Eligible patients had previously treated CLL/SLL or another type of B-cell NHL, with active disease that required treatment. Endpoints included efficacy and safety, as well as determinations of the maximum tolerated dose and the recommended phase 2 dose.
The 170 patients with CLL/SLL were a median age of 69 years (range, 36-88).8 They had received a median of 3 prior systemic therapies (range, 1-11). Unmutated IGHV was present in 88% of the patients. At daily doses of 100 mg or higher, the plasma concentration of LOXO-305 exceeded the BTK 90% maximal inhibitory concentration (IC90) throughout the dosing interval. The investigators identified a linear relationship between the dose level and the plasma concentration.
Among the 323 patients with NHL in the study, no dose-limiting toxicities occurred, and the maximum tolerated dose was not reached. Treatment-related AEs led 5 patients (1.5%) to discontinue LOXO-305. The most common treatment-related AEs of any grade, observed in at least 10% of patients, were fatigue (20%), diarrhea (17%), and contusion (13%). AEs of special interest were almost all grade 1/2. Exceptions included hemorrhage (all cases grade 3; <1%) and hypertension (all cases grade 3; 1%). The recommended phase 2 dose was 200 mg daily.
In the cohort of patients with CLL/SLL, the ORR was 63%, including a 50% PR rate and a 14% rate of PR with lymphocytosis.8 The ORR improved from the end of treatment through 10 months afterward (Figure 7). After a median follow-up of 6 months, 94% of the patients who initially responded to treatment maintained the response. Promising efficacy outcomes were observed in the subgroups of patients with previous exposure to a BTK inhibitor or other therapy, as well as in patients with a BTKC481S mutation.
The BRUIN study also included 61 patients with mantle cell lymphoma, 26 with Waldenström macroglobulinemia, and 66 with another NHL subtype.9 These patients were a median age of 68 years (range, 27-87). Previous use of BTK therapy was reported among 93% of the patients with mantle cell lymphoma, 69% of those with Waldenström macroglobulinemia, and 37% of those with other NHL subtypes.
In the 56 patients with mantle cell lymphoma evaluable for response, the ORR was 52%, including a CR rate of 25%.9 Among these patients, a response was maintained in 83% after a median follow-up of 6 months. Among the patients with Waldenström macroglobulinemia, the ORR was 68%, including a PR rate of 47% and a minimal response rate of 21%. Among the patients with other NHL subtypes, the ORR was 22% in those with MZL, 24% in those with diffuse large B-cell lymphoma, 50% in those with follicular lymphoma, and 75% in those with Richter transformation. As of September 27, 2020, responses were ongoing in 77% (10/13) of the patients with Waldenström macroglobulinemia and 83% (5/6) of those with Richter transformation.
References
1. Burger JA, Barr PM, Robak T, et al. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia. 2020;34(3):787-798.
2. Byrd JC, Harrington B, O’Brien S, et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):323-332.
3. Hershkovitz-Rokah O, Pulver D, Lenz G, Shpilberg O. Ibrutinib resistance in mantle cell lymphoma: clinical, molecular and treatment aspects. Br J Haematol. 2018;181(3):306-319.
4. Lampson BL, Brown JR. Are BTK and PLCG2 mutations necessary and sufficient for ibrutinib resistance in chronic lymphocytic leukemia? Expert Rev Hematol. 2018;11(3):185-194.
5. Woyach JA, Furman RR, Liu TM, et al. Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014;370(24):2286-2294.
6. Woyach JA, Ruppert AS, Guinn D, et al. BTKC481S-mediated resistance to ibrutinib in chronic lymphocytic leukemia. J Clin Oncol. 2017;35(13):1437-1443.
7. Brandhuber B, Gomez E, Smith S, et al. LOXO-305, a next generation reversible BTK inhibitor, for overcoming acquired resistance to irreversible BTK inhibitors [SHO abstract S216]. Clin Lymphoma Myeloma Leuk. 2018;18(suppl 1).
8. Mato A, Flinn IW, Pagel JM, et al. Results from a first-in-human, proof-of-concept phase 1 trial in pretreated B-cell malignancies for LOXO-305, a next-generation, highly selective, non-covalent BTK inhibitor [ASH abstract 501]. Blood. 2019;134(suppl 1).
9. Wang ML, Shah NN, Alencar AJ, et al. LOXO-305, a next generation, highly selective, non-covalent BTK inhibitor in previously treated mantle cell lymphoma, Waldenström’s macroglobulinemia, and other non-Hodgkin lymphomas: results from the phase 1/2 BRUIN study [ASH abstract 117]. Blood. 2020;136(suppl 1).
Umbralisib, the Once Daily Dual Inhibitor of PI3Kδ and Casein Kinase-1ε, Demonstrates Clinical Activity in Patients With Relapsed or Refractory Indolent Non-Hodgkin Lymphoma: Results From the Phase 2 Global UNITY-NHL Trial
The international phase 2 UNITY-NHL trial evaluated umbralisib monotherapy in previously treated patients.1 Eligible patients were adults with histologically confirmed MZL, follicular lymphoma, or SLL that had progressed after at least 2 prior lines of therapy. Umbralisib (800 mg) was administered daily until the patient developed disease progression, experienced unacceptable toxicity, or withdrew from the study. The first response assessment occurred at the end of cycle 3. The primary endpoint was the ORR, assessed by independent review. The study included 69 patients with MZL, 117 with follicular lymphoma, and 22 with SLL. The median age was 66 years (range, 29-88). All patients had received prior treatment with an anti-CD20 agent, 77% had stage 3/4 disease, and 34% had disease that was refractory to the most recent therapy. The median number of prior therapies was 2 (range, 1-10). The median follow-up was 27.7 months.
The ORR was 49.3% (16% CR rate) in patients with MZL, 45.3% (5% CR rate) in those with follicular lymphoma, and 50.0% (5% CR rate) in those with SLL.1 Across the entire study population of 208 patients, umbralisib yielded an ORR of 47.1% and a disease control rate of 81.3%. Encouraging response rates were observed in patients who had received more than 3 prior lines of therapy and in patients with various MZL subtypes. The ORR in patients with follicular lymphoma was 57% for those with grade 1 disease, 45% for those with grade 2 disease, and 34% for those with grade 3A disease. The median decrease in the size of the index lesion was 90.6% in patients with MZL, 83.5% in those with follicular lymphoma, and 89.5% in those with SLL. The median DOR was not reached in the patients with MZL, 11.1 months in those with follicular lymphoma, and 18.3 months in those with SLL (Figure 8). The median PFS was not reached, 10.6 months, and 20.9 months in the 3 cohorts, respectively. Disease progression did not occur in any of the 11 patients with MZL who had a CR.
Umbralisib monotherapy was generally well tolerated in the overall study population.1 The most common AEs of any grade were diarrhea (59.1%), nausea (39.4%), and fatigue (30.8%). The safety profile of umbralisib was distinct from that of other PI3K inhibitors. AEs of special interest to the investigators were generally uncommon. Transaminase elevations led 2.9% of patients to discontinue therapy, and another 2.9% of patients discontinued treatment after experiencing grade 3 diarrhea. Noninfectious colitis was documented in 4 patients; this event resolved in 3 of them, who continued treatment with umbralisib. Other AEs of special interest included grade 3/4 opportunistic infections (3.4%), grade 3/4 rash (1.9%), and grade 3/4 pneumonitis (1.0%).
Reference
1. Zinzani P, Samaniego F, Jurczak W, et al. Umbralisib, the once daily dual inhibitor of Pi3Kδ and casein kinase-1ε demonstrates clinical activity in patients with relapsed or refractory indolent non-hodgkin lymphoma: results from the phase 2 global UNITY-NHL trial [ASH abstract 2934]. Blood. 2020;136(suppl 1).
Clinical Activity of TG-1701, as Monotherapy and in Combination With Ublituximab and Umbralisib (U2), in Patients With B-Cell Malignancies
TG-1701 is a covalent inhibitor of BTK with better binding selectivity than ibrutinib.1 The combination of U2 plus TG-1701 inhibited tumor growth in a mouse model harboring BTK-resistant xenografts.2 A phase 1 study evaluated TG-1701, alone or in combination with U2, in patients with B-cell NHL or CLL.3 Key objectives included characterizing the safety profile of TG-1701, determining the recommended phase 2 dose of TG-1701 as monotherapy or in combination with U2, and evaluating pharmacokinetics. Most patients had relapsed or refractory disease. Treatment-naive patients were enrolled if standard frontline chemotherapy was not an option.
Treatment with TG-1701 monotherapy was administered daily in doses ranging from 100 to 400 mg.3 When TG-1701 was combined with the U2 regimen, the daily dose ranged from 100 to 400 mg. TG-1701 at a daily dose of 200 mg was given to 3 disease-specific cohorts: 20 patients with CLL, 20 with Waldenström macroglobulinemia, and 21 with mantle cell lymphoma; some of these patients were treatment-naive. Seventeen patients with CLL who received TG-1701 at a daily dose of 300 mg comprised another cohort. Intra-patient dose escalation was allowed.
In the monotherapy arm, after a median follow-up of 14 months (range, 1-25), the ORR was 52% (12/23).3 Across the disease-specific cohorts treated with 200 mg/day of TG-1701, after a median follow-up of 7 months, the ORR was 95% in patients with CLL, 95% in patients with Waldenström macroglobulinemia, and 50% in those with mantle cell lymphoma. In 14 patients treated with the U2 regimen and escalating doses of TG-1701, after a median follow-up of 12 months, the ORR was 79%, with a 22% CR rate (Figure 9). Durable responses were observed with monotherapy and the combination.
The safety profile of TG-1701 monotherapy was manageable, with no grade 4 AEs.3 The most common AEs of any grade were constipation (32%), respiratory tract infection (28%), and bruising (28%). The most common hematologic and laboratory abnormalities included neutropenia (24%), increased alanine transaminase (24%), and increased aspartate transaminase (20%). Among 16 patients treated with TG-1701 plus U2, the most common AEs diarrhea (44%), infusion-related reaction (38%), and bruising (38%). Grade 4 AEs were rare. The maximum tolerated dose was not reached in the monotherapy arm.
References
1. Normant E, Gorelik L, Shmeis R, et al. TG-1701 a novel, orally available, and covalently bound BTK inhibitor [EHA abstract PF638]. Hemasphere. 2018;2(S1).
2. Ribeiro ML, Reyes-Garau D, Vinyoles M, et al. TG-1701, a novel irreversible Bruton’s kinase (BTK) inhibitor, cooperates with ublituximab-driven ADCC and ADCP in in vitro and in vivo models of ibrutinib-resistant mantle cell lymphoma [AACR abstract 2205]. Cancer Res. 2020;80(16 suppl).
3. Cheah CY, Wickham N, Jurczak W, et al. Clinical activity of TG-1701, as monotherapy and in combination with ublituximab and umbralisib (U2), in patients with B-cell malignancies [ASH abstract 1130]. Blood. 2020;136(suppl 1).
Phase II Study of Pembrolizumab Plus GVD As Second-Line Therapy for Relapsed or Refractory Classical Hodgkin Lymphoma
Among patients with Hodgkin lymphoma, the goal of second-line therapy is to achieve a CR, according to positron emission tomography (PET), so patients can undergo autologous hematopoietic stem cell transplant (SCT). 1 Autologous SCT is most likely to cure Hodgkin lymphoma when the second-line regimen induces a CR.2,3 However, second-line therapy fails to achieve a CR in up to half of patients.
A phase 2 trial evaluated pembrolizumab combined with gemcitabine, vinorelbine, and liposomal doxorubicin (GVD) in patients with relapsed or refractory Hodgkin lymphoma after first-line treatment.4,5 Standard GVD was administered on days 1 and 8, and pembrolizumab (200 mg) was administered on day 1 of each 21-day cycle. Patients with a CR according to PET imaging after 2 cycles were eligible for autologous hematopoietic SCT. Responses were assessed again by PET after cycle 4. The primary endpoint was the CR rate (based on a Deauville score of 3) after 2 or 4 cycles of treatment.6,7 The 39 enrolled patients were a median age of 38 years (range, 21-71), and 59% had stage 3/4 disease at baseline. A CR had not been achieved with first-line therapy in 41% of the patients, and 38% had experienced a relapse within 1 year of initial treatment. The most common first-line therapy was doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD; 69%), followed by brentuximab vedotin plus AVD (21%).
The median follow-up was 11.2 months (range, 0.95-24).8 There were 37 evaluable patients. After treatment with pembrolizumab plus GVD for 2 cycles, a CR was reported in 34 patients (92%), and a PR occurred in 3 patients (85%). Among 7 patients who received an additional 2 cycles of pembrolizumab plus GVD, 4 CRs were maintained, 1 new CR occurred, and 2 PRs were maintained. Overall, a CR was reported in 35 of 37 patients (95%). A total of 35 patients (95%) proceeded to autologous hematopoietic SCT, and 11 of these patients received brentuximab vedotin as part of consolidation treatment.8 No patients developed progressive disease. The CR rate with pembrolizumab plus GVD was therefore higher than the 67% CR rate reported in the CheckMate 205 study, which evaluated nivolumab plus AVD in previously untreated patients.9
Treatment was generally well tolerated, with few high-grade AEs.8 Grade 3 AEs included elevated transaminase levels in 3 patients (8%), and neutropenia in 3 patients (8%). An additional cohort is being enrolled to evaluate the same regimen followed by pembrolizumab maintenance therapy. Patients with a CR after 4 cycles of pembrolizumab plus GVD will receive up to 13 cycles of pembrolizumab.
References
1. Sureda A, André M, Borchmann P, et al. Improving outcomes after autologous transplantation in relapsed/refractory Hodgkin lymphoma: a European expert perspective. BMC Cancer. 2020;20(1):1088.
2. Moskowitz AJ, Yahalom J, Kewalramani T, et al. Pretransplantation functional imaging predicts outcome following autologous stem cell transplantation for relapsed and refractory Hodgkin lymphoma. Blood. 2010;116(23):4934-4937.
3. Schmitz N, Pfistner B, Sextro M, et al; German Hodgkin’s Lymphoma Study Group; Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin’s disease: a randomised trial. Lancet. 2002;359(9323):2065-2071.
4. Moskowitz AJ, Shah G, Schoder H, et al. Phase II study of pembrolizumab plus GVD as second-line therapy for relapsed or refractory classical Hodgkin lymphoma [ASH abstract 407]. Blood. 2020;136(suppl 1).
5. Galluzzi L, Senovilla L, Zitvogel L, Kroemer G. The secret ally: immunostimulation by anticancer drugs. Nat Rev Drug Discov. 2012;11(3):215-233.
6. Barrington SF, Kirkwood AA, Franceschetto A, et al. PET-CT for staging and early response: results from the Response-Adapted Therapy in Advanced Hodgkin Lymphoma study. Blood. 2016;127(12):1531-1538.
7. Biggi A, Gallamini A, Chauvie S, et al. International validation study for interim PET in ABVD-treated, advanced-stage hodgkin lymphoma: interpretation criteria and concordance rate among reviewers. J Nucl Med. 2013;54(5):683-690.
8. Moskowitz CH, Nademanee A, Masszi T, et al; AETHERA Study Group. Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin’s lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2015;385(9980):1853-1862.
9. Ramchandren R, Domingo-Domènech E, Rueda A, et al. Nivolumab for newly diagnosed advanced-stage classic Hodgkin lymphoma: safety and efficacy in the phase II CheckMate 205 study. J Clin Oncol. 2019;37(23):1997-2007.
Efficacy and Safety Results From ASCEMBL, a Multicenter, Open-Label, Phase 3 Study of Asciminib, a First-in-Class STAMP Inhibitor, vs Bosutinib in Patients With Chronic Myeloid Leukemia in Chronic Phase Previously Treated With ≥2 Tyrosine Kinase Inhibitors
Asciminib is a tyrosine kinase inhibitor (TKI) that binds to the myristoyl pocket of ABL1 and the BCR-ABL1 oncoprotein.1-3 Owing to its unique binding site and mechanism of action, asciminib is predicted to bind with much less affinity to other tyrosine kinase proteins and therefore should have fewer off-target toxicities. Bosutinib binds to the ATP-binding site of ABL1, a mechanism shared by other approved TKIs, and is approved for the treatment of chronic-phase chronic myeloid leukemia.4-7 Bosutinib has demonstrated efficacy in clinical trials of patients with chronic myeloid leukemia that had been treated with 2 or more TKIs before enrollment.
The phase 2 ASCEMBL study compared asciminib (40 mg twice daily) vs bosutinib (500 mg once daily) in adults with chronic-phase chronic myeloid leukemia.8 Eligible patients had received prior treatment with at least 2 TKIs, and their most recent TKI had failed or was not tolerable. Patients who could not tolerate their most recent TKI were required to have evidence of the BCR-ABL1IS transcript at screening. Patients were stratified by major cytogenetic response and then randomly assigned in a 2:1 ratio to receive asciminib or bosutinib. Patients with a bosutinib-resistant T315I or V299L mutation were excluded from enrollment. When bosutinib failed, patients were able to switch to the asciminib arm at the investigator’s discretion. The primary endpoint was major molecular response (MMR) at 24 weeks during treatment in patients who did not meet any treatment failure criteria before 24 weeks.
The trial included 157 patients in the asciminib arm and 76 in the bosutinib arm.8 The patients had a median age of 52 years (range, 19-83). The most common reasons for discontinuation of the most recent TKI therapy were lack of efficacy (64%) and lack of tolerability (35%). In the asciminib and bosutinib arms, 48% and 61% of patients, respectively, had received 3 or more prior TKI therapies. At cutoff, treatment was ongoing in 62% of patients in the asciminib arm vs 30% of patients in the bosutinib arm. Among the patients randomly assigned to the bosutinib arm, 29% had switched to the asciminib arm.
The median follow-up was 14.9 months after randomization.8 The MMR rate at 24 weeks was 25.5% with asciminib vs 13.2% with bosutinib, a treatment difference of 12.2% (95% CI, 2.19%-22.3%; P=.029) after adjustment for major cytogenetic response status at baseline. The median duration of exposure was 43.4 weeks (range, 0.1-129.9) with asciminib vs 29.2 weeks (range, 1.0-117.0) with bosutinib. The cumulative incidence of MMR is shown in Figure 10. At 24 weeks, the MMR rate was better with asciminib vs bosutinib in most subgroups, including those defined by major cytogenetic response status, sex, outcome with prior TKI treatment, lines of therapy, and BCR-ABL1 mutation status at baseline.8 Asciminib was superior to bosutinib after adjustment for patient variables such as major cytogenetic response status (odds ratio, 2.35; 95% CI, 1.08-5.12).
After 12 weeks of study treatment, differences arose between the rates of MMR reported in the 2 arms. Among patients without a complete cytogenetic response at baseline, the complete cytogenetic response rate at 24 weeks was 40.8% with asciminib vs 24.2% with bosutinib (95% CI, 3.62%-31.0%) after adjustment for major cytogenetic response status at baseline.
More patients in the bosutinib arm discontinued treatment owing to an AE (21.1% vs 5.8%).8 Dose interruptions were also more common in the bosutinib arm (60.5% vs 37.8%), as were AEs requiring additional therapy (88.2% vs 66.0%). Fatal AEs occurred in 1.3% of patients in each arm. AEs of any grade that were more common in the asciminib arm included thrombocytopenia (28.8%) and neutropenia (21.8%). The most common AEs of any grade in the bosutinib arm were observed less frequently in the asciminib arm. These AEs included diarrhea (71.1% vs 11.5%), nausea (46.1% vs 11.5%), and rash (23.7% vs 7.1%). Arterial occlusive events were more common in the asciminib arm (3.2% vs 1.3%).
References
1. Manley PW, Barys L, Cowan-Jacob SW. The specificity of asciminib, a potential treatment for chronic myeloid leukemia, as a myristate-pocket binding ABL inhibitor and analysis of its interactions with mutant forms of BCR-ABL1 kinase. Leuk Res. 2020;98:106458.
2. Schoepfer J, Jahnke W, Berellini G, et al. Discovery of asciminib (ABL001), an allosteric inhibitor of the tyrosine kinase activity of BCR-ABL1. J Med Chem. 2018;61(18):8120-8135.
3. Wylie AA, Schoepfer J, Jahnke W, et al. The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1. Nature. 2017;543(7647):733-737.
4. Cortes JE, Khoury HJ, Kantarjian HM, et al. Long-term bosutinib for chronic phase chronic myeloid leukemia after failure of imatinib plus dasatinib and/or nilotinib. Am J Hematol. 2016;91(12):1206-1214.
5. Hochhaus A, Gambacorti-Passerini C, Abboud C, et al; BYOND Study Investigators. Bosutinib for pretreated patients with chronic phase chronic myeloid leukemia: primary results of the phase 4 BYOND study. Leukemia. 2020;34(8):2125-2137.
6. Khoury HJ, Cortes JE, Kantarjian HM, et al. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood. 2012;119(15):3403-3412.
7. Bosulif [package insert]. New York, NY: Pfizer, Inc; 2019.
8. Hochhaus A, Boquimpani B, Réa D, et al. Efficacy and safety results from ASCEMBL, a multicenter, open-label, phase 3 study of asciminib, a first-in-class stamp inhibitor, vs bosutinib (bos) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-cp) previously treated with ≥2 tyrosine kinase inhibitors (TKIs) [ASH abstract LBA-4]. Blood. 2020;136(suppl 1).
Highlights in Leukemia and Lymphoma From the 62nd American Society of Hematology Annual Meeting and Exposition: Commentary
Paul M. Barr, MD
Medical Director, Clinical Trial Office
Professor of Medicine
James P. Wilmot Cancer Institute, University of Rochester Medical Center
Rochester, New York
Many studies presented at the 62nd American Society of Hematology meeting provided important new data on leukemia and lymphoma. Here, I focus on a few abstracts that stand out, acknowledging that this list is not comprehensive.
Umbralisib and Ublituximab
Dr John Gribben presented results from the UNITY-CLL study of umbralisib and ublituximab, a regimen known as U2.1 This notable abstract provided some of the first randomized, high-level, pivotal phase 2 data for this regimen. Umbralisib is an inhibitor of phosphatidylinositol 3-kinase delta (PI3Kδ) and casein kinase 1 epsilon (CK1ε). Previous data suggested that umbralisib is an efficacious PI3K inhibitor, with perhaps a better safety profile compared with other drugs in this class.2 The trial enrolled patients with untreated or previously treated chronic lymphocytic leukemia (CLL). The primary outcome was progression-free survival (PFS). The study found a PFS benefit for the investigational U2 arm compared with chlorambucil plus obinutuzumab. The median PFS was 31.9 months vs 17.9 months, respectively (P<.0001). This outcome was unsurprising; many studies have shown that novel agents are superior to chlorambucil-based therapy. The take-home point was that the U2 regimen led to a median PFS of 38.5 months in previously untreated patients and 19.5 months in patients with relapsed/refractory disease. The rate of grade 3 diarrhea was approximately 12% in the U2 arm. Toxicity can be a concern with PI3K inhibitors, which have been associated with high rates in previous trials.3 In the UNITY-CLL trial, few patients in the U2 arm discontinued treatment after developing diarrhea. The rest of the side effect profile suggested reasonable tolerability.
These data suggest that the combination of umbralisib and ublituximab is efficacious in patients with CLL. Cross-trial comparisons might suggest that the combination does not appear quite as strong as the Bruton tyrosine kinase (BTK) inhibitors.4,5 Nonetheless, there is a potential role for ublituximab plus umbralisib in CLL, perhaps initially in patients with relapsed disease. The combination might be useful in the community setting, given that the agents are reasonably easy to administer compared with a drug such as venetoclax.
My colleagues and I presented data for a phase 1/2 study of U2 plus venetoclax in patients with relapsed or refractory CLL.6 This study is being conducted at 3 different centers. More than 40 patients have been enrolled. The idea behind this triplet regimen is to administer therapy for a defined period, rather than subjecting patients to unending treatment. The regimen was evaluated in relapsed patients, given the widespread use of BTK inhibitors in the first-line setting.
Data on 43 patients treated to date were presented. After 12 cycles of therapy, all patients have responded. More than three-quarters of patients have undetectable minimal residual disease in the blood and bone marrow. These early results are promising. In the relapsed setting, this triplet regimen might compare well with regimens such as venetoclax plus rituximab, which was studied in the MURANO trial.7
Dr Pier Luigi Zinzani presented the initial results from the UNITY-NHL study, which evaluated umbralisib in patients with relapsed or refractory non-Hodgkin lymphoma (NHL).8 UNITY-NHL is the pivotal registrational trial for umbralisib in indolent non-Hodgkin lymphoma. The trial enrolled 117 patients with follicular lymphoma, 69 with marginal zone lymphoma, and 22 with small lymphocytic lymphoma (SLL). In the follicular lymphoma cohort, the patients had received a median of 3 prior lines of therapy, and thus were heavily pretreated. Patients with marginal zone lymphoma had received a median of 2 prior therapies. In both of these cohorts, the overall response rate was a little less than 50%. These data are similar to those reported for the other PI3K inhibitors—idelalisib, duvelisib, and copanlisib. A difference is that more patients were able to continue treatment with umbralisib. Toxicity led to low rates of treatment discontinuation, supporting my previous comment that umbralisib appears to have a more favorable safety profile than the other PI3K inhibitors. The rate of grade 3 diarrhea was 10%, but only 2.9% of patients discontinued therapy owing to this event. These rates are similar to those reported in the UNITY-CLL study.1 Although it will be necessary to monitor for PI3K inhibitor–related side effects during treatment with umbralisib, this drug appears to be well-tolerated overall. Umbralisib could therefore be useful in patients with relapsed/refractory follicular lymphoma, now that the agent is approved by the US Food and Drug Administration in this setting. No other PI3K inhibitors are approved for marginal zone lymphoma, so umbralisib could have an impact here as well.
LOXO-305
The phase 1/2 BRUIN trial is evaluating LOXO-305, an investigational, next-generation BTK inhibitor in patients with previously treated CLL/SLL or NHL. LOXO-305 binds in a noncovalent reversible fashion, which differs from the other BTK inhibitors (ibrutinib, acalabrutinib, and zanubrutinib). Dr Anthony Mato presented data for patients with CLL.9 The patients with CLL were heavily pretreated. Approximately 86% had already received a covalent BTK inhibitor. When these patients develop resistance, more than half have identifiable BTK or PLCc mutations.10 Despite this resistance, the results were impressive, with an overall response rate of 63%. The median follow-up was relatively short, at 6 months. There were low rates of BTK-related side effects, including atrial fibrillation and grade 3 hemorrhage.
The waterfall plot suggests that most of the patients responded. With further follow-up, the response rate may continue to improve, and the duration of response could be significant. Many investigators will monitor this trial closely, given the promising results presented to date.
Dr Michael Wang presented data for LOXO-305 in patients with mantle cell lymphoma, Waldenström macroglobulinemia, and other types of NHL.11 Most patients had mantle cell lymphoma. The patients were heavily pretreated. They had received a median of 3 prior therapies, including BTK inhibitors in 93%. The response rate was 52%, which is promising given the poor outcomes that patients can experience after treatment with other BTK inhibitors. Responses were ongoing in 83%. Again, the follow-up was short, at approximately 6 months. Among the patients with Waldenström macroglobulinemia, approximately two-thirds had received prior BTK inhibitors. The response rate in this cohort was 68%, with three-quarters of the responses ongoing. Notably, among 8 patients with Richter transformation, there were 6 responses. Based on the data from both of these abstracts, LOXO-305 has promising efficacy across the lymphoma subtypes studied.
Chimeric Antigen Receptor (CAR) T-Cell Therapy
Dr Caron Jacobson presented updated data for the ZUMA-5 study of axicabtagene ciloleucel in patients with relapsed/refractory indolent NHL, specifically follicular lymphoma and marginal zone lymphoma.12 Earlier data were presented at the 2020 American Society of Clinical Oncology meeting.13 Axicabtagene ciloleucel is a CAR T-cell product that is approved for the treatment of aggressive lymphomas, including diffuse large B-cell lymphoma and high-grade B-cell lymphoma. This presentation included efficacy data for 104 patients: 84 with follicular lymphoma and 20 with marginal zone lymphoma. The median follow-up was 18 months. These heavily pretreated patients had received a median of 2 prior lines of therapy. More than half had developed progressive disease within 24 months of treatment with an alkylating agent–based regimen. Approximately one-quarter of patients had undergone a prior autologous stem cell transplant.
Among the patients with follicular lymphoma, the complete response rate was 80%. At 1 year, 78% of the patients were without progression and still alive. The complete response rate was 60% among patients with marginal zone lymphoma, but these data are less mature. The side effect profile was mostly similar to that seen in studies of aggressive lymphomas.14 The rates of grade 3 or higher cytokine release syndrome were somewhat lower, at 7%. Grade 3 or higher neurologic events occurred in 19%.
There are many therapeutic options for patients with follicular lymphoma and marginal zone lymphoma. Overall, these patients have an indolent disease course and therefore a relatively good prognosis. Additionally, CAR T-cell therapy will not be an option for all of these older patients. Nonetheless, axicabtagene ciloleucel—and CAR T-cell therapy in general—could have an impact in high-risk patients with these lymphoma histologies given the potential for long-term remissions. It is possible to envision the use of CAR T-cell therapy in patients with an early relapse or heavily pretreated disease.
The phase 2 ZUMA-12 trial evaluated axicabtagene ciloleucel as first-line therapy in patients with high-risk large B-cell lymphoma.15 Axicabtagene ciloleucel is approved for the treatment of relapsed/refractory diffuse large B-cell lymphoma and other aggressive lymphoma histologies. Approximately 40% of these patients can develop durable remissions after receiving axicabtagene ciloleucel despite being heavily pretreated.14 In ZUMA-12, the strategy investigated was to intervene early in patients who appeared to have an inferior response to first-line chemoimmunotherapy. The trial enrolled patients with high-grade B-cell lymphoma; more than half had double-hit or triple-hit lymphoma. Nearly three-quarters of patients had an International Prognostic Index (IPI) score of 3 or higher. All patients had received 2 cycles of induction therapy, which had not led to a complete remission. Their Deauville score was 4 or 5 after treatment with regimens such as rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone.
The primary endpoint was complete response. Dr Sattva Neelapu presented data for 27 evaluable patients.15 The evaluable population included all treated patients with centrally confirmed disease (double-hit or triple-hit lymphoma) or an IPI score of 3 who had received at least 1 × 106 CAR T cells/kg and had at least 1 month of follow-up. Treatment with axicabtagene ciloleucel led to a complete response rate of 74%. At a short follow-up of 9 months, 70% of patients had an ongoing response. The toxicity profile was similar to that seen in ZUMA-1, the study that led to the approval of axicabtagene ciloleucel.14
The ZUMA-12 study requires additional follow-up. A subsequent randomized study is also needed to determine if this strategy will improve patient survival in the first-line setting. However, in this population of patients without an adequate response to earlier therapy, a complete remission rate of 74% is promising. Clinicians are excited to see how these data mature over time.
Gemcitabine, Vinorelbine, and Doxorubicin Plus Pembrolizumab
Dr Alison Moskowitz presented results from a phase 2 study of gemcitabine, vinorelbine, and liposomal doxorubicin (GVD) plus pembrolizumab as second-line therapy for relapsed or refractory classical Hodgkin lymphoma.16 Historically, patients with Hodgkin lymphoma have a relatively good prognosis. Among patients with advanced-stage disease, approximately 70% to 75% are cured with therapy such as doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD).17 For the patients who relapse, the goal of a second-line regimen is to achieve a complete response or positron emission tomography (PET) negativity. Historically, treatment with chemotherapy has been associated with complete response rates of approximately 50% to 60%.18,19 More recently, the addition of brentuximab vedotin increased these rates to 65% to 80%.20,21
In the study by Dr Moskowitz, GVD plus pembrolizumab could be given for up to 4 cycles.16 The primary endpoint was PET negativity or complete response. Among the 39 enrolled patients, 41% were primary refractory, meaning they had not achieved a complete remission with ABVD-like therapy. The presentation provided data for 27 patients. After 2 cycles of therapy, 92% of the patients had achieved a complete response. There was 1 additional complete response with another 2 cycles of therapy, for an impressive complete response rate of 95%. Thirty-five of the patients underwent stem cell transplant. After a median follow-up of 11 months, no patients developed progressive disease.
This rate of complete response to a second-line regimen is unprecedented, albeit reported in a relatively small group of patients. It is a higher rate than that seen when programmed death 1 inhibitors were added to first-line therapy in the trial of doxorubicin, vinblastine, and dacarbazine plus nivolumab.22 These data suggest that the combination of pembrolizumab with gemcitabine-based therapy is worth exploration. The investigators will evaluate this regimen further, perhaps considering a transplant-free approach. Given such a high rate of complete response, it may be possible for these patients to achieve a durable remission with this regimen followed by pembrolizumab maintenance for a year, and thereby avoid stem cell transplant.
Disclosure
Dr Barr has performed consulting for Pharmacyclics/AbbVie, Genentech, Gilead, Merck, TG Therapeutics, AstraZeneca, Celgene/BMS, MorphoSys, Janssen, BeiGene, Seattle Genetics, and Bayer. He has received research funding from AstraZeneca and TG Therapeutics.
References
1. Gribben J, Jurczak W, Jacobs R, et al. Umbralisib plus ublituximab (U2) is superior to obinutuzumab plus chlorambucil (O+Chl) in patients with treatment naïve (TN) and relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): results from the phase 3 UNITY-CLL study [ASH abstract 543]. Blood. 2020;136(suppl 1).
2. Janovská P, Normant E, Miskin H, Bryja V. Targeting casein kinase 1 (CK1) in hematological cancers. Int J Mol Sci. 2020;21(23):E9026.
3. Lampson BL, Kim HT, Davids MS, et al. Efficacy results of a phase 2 trial of first-line idelalisib plus ofatumumab in chronic lymphocytic leukemia. Blood Adv. 2019;3(7):1167-1174.
4. Munir T, Brown JR, O’Brien S, et al. Final analysis from RESONATE: up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma. Am J Hematol. 2019;94(12):1353-1363.
5. Burger JA, Barr PM, Robak T, et al. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia. 2020;34(3):787-798.
6. Barr PM, Ma S, Zent CS, et al. A phase 1/2 study of umbralisib, ublituximab, and venetoclax (U2-ven) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) [ASH abstract 3137]. Blood. 2020;136(suppl 1).
7. Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378(12):1107-1120.
8. Zinzani P, Samaniego F, Jurczak W, et al. Umbralisib, the once daily dual inhibitor of Pi3Kδ and casein kinase-1ε demonstrates clinical activity in patients with relapsed or refractory indolent non-Hodgkin lymphoma: results from the phase 2 global UNITY-NHL trial [ASH abstract 2934]. Blood. 2020;136(suppl 1).
9. Mato AR, Pagel JM, Coombs CC, et al. LOXO-305, a next generation, highly selective, non-covalent BTK inhibitor in previously treated CLL/SLL: results from the phase 1/2 BRUIN study [ASH abstract 542]. Blood. 2020;136(suppl 1).
10. Woyach JA, Ruppert AS, Guinn D, et al. BTK C481S-mediated resistance to ibrutinib in chronic lymphocytic leukemia. J Clin Oncol. 2017;35(13):1437-1443.
11. Wang ML, Shah NN, Alencar AJ, et al. LOXO-305, a next generation, highly selective, non-covalent btk inhibitor in previously treated mantle cell lymphoma, Waldenström’s macroglobulinemia, and other non-Hodgkin lymphomas: results from the phase 1/2 BRUIN study [ASH abstract 117]. Blood. 2020;136(suppl 1).
12. Jacobson CA, Chavez JC, Sehgal AR, et al. Primary analysis of ZUMA-5: a phase 2 study of axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory (R/R) indolent non-hodgkin lymphoma (iNHL) [ASH abstract 700]. Blood. 2020;136(suppl 1).
13. Jacobson CA, Chavez JC, Sehgal AR, et al. Interim analysis of ZUMA-5: a phase II study of axicabtagene ciloleucel (axi-cel) in patients (pts) with relapsed/refractory indolent non-Hodgkin lymphoma (R/R iNHL) [ASCO abstract 8008]. J Clin Oncol. 2020;38(15 suppl).
14. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531-2544.
15. Neelapu SS, Dickinson M, Ulrickson ML, et al. Interim analysis of ZUMA-12: a phase 2 study of axicabtagene ciloleucel (axi-cel) as first-line therapy in patients (pts) with high-risk large B cell lymphoma (LBCL) [ASH abstract 405]. Blood. 2020;136(suppl 1).
16. Moskowitz AJ, Shah G, Schoder H, et al. Phase II study of pembrolizumab plus GVD as second-line therapy for relapsed or refractory classical Hodgkin lymphoma [ASH abstract 470]. Blood. 2020;136(suppl 1).
17. Strati P, Fanale MA, Oki Y, et al. ABVD plus rituximab versus ABVD alone for advanced stage, high-risk classical Hodgkin lymphoma: a randomized phase 2 study. Haematologica. 2019;104(2):e65-e67.
18. Moskowitz CH, Matasar MJ, Zelenetz AD, et al. Normalization of pre-ASCT, FDG-PET imaging with second-line, non-cross-resistant, chemotherapy programs improves event-free survival in patients with Hodgkin lymphoma. Blood. 2012;119(7):1665-1670.
19. Santoro A, Magagnoli M, Spina M, et al. Ifosfamide, gemcitabine, and vinorelbine: a new induction regimen for refractory and relapsed Hodgkin’s lymphoma. Haematologica. 2007;92(1):35-41.
20. Moskowitz AJ, Advani R, Bartlett NL, et al. 2-Year follow-up results from the phase 1-2 study of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma [ASH abstract 238]. Blood. 2019;134(suppl 1).
21. Herrera AF, Palmer J, Martin P, et al. Autologous stem-cell transplantation after second-line brentuximab vedotin in relapsed or refractory Hodgkin lymphoma. Ann Oncol. 2018;29(3):724-730.
22. Bröckelmann PJ, Goergen H, Keller U, et al. Efficacy of nivolumab and AVD in early-stage unfavorable classic Hodgkin lymphoma. The randomized phase 2 German Hodgkin Study Group NIVAHL trial. JAMA Oncol. 2020;6(6):872-880.