Following the 2019 ASH Annual Meeting, Targeted Oncology spoke with experts from various specialties in hematology. The experts highlighted some of the top abstracts from the meeting that will impact the way multiple myeloma, leukemias, MPNs, and lymphomas are treated.
stAmerican Society of Hematology (ASH) Annual Meeting, which took place December 7 10, 2019, in Orlando, Florida. Experts from around the world flocked to the Sunshine Sate to get the latest data from clinical trials in various hematologic malignancies and diseases.
Targeted Oncologyfollowers on social media shared their thoughts in a Twitter poll that asked in which area had the most important data during this year’s meeting. With so many updates across hematologic malignancies, multiple myeloma appeared to have the most interest, according to the Twitter poll, followed by lymphomas, myeloproliferative neoplasms (MPNs), and leukemias.
ASH POLL: In what area do you think the most important data came from at the 2019@ASH_HematologyMeeting? Tell us in the comments what your top#ASH19abstracts were and tag colleagues for their opinions, too!
Look back on some of the abstracts here:https://t.co/0PRPg4sAEX
Targeted Oncology (@TargetedOnc)December 9, 2019
Following the 2019 ASH Annual Meeting,Targeted Oncologyspoke with experts from various specialties in hematology. The experts highlighted some of the top abstracts from the meeting that will impact the way multiple myeloma, leukemias, lymphomas, and MPNs are treated.
Andrew J. Cowan, MD
CARTITUDE-1 Trial Reports 100% Response Rate in Heavily Pretreated Myeloma
The phase Ib/II CARTITUDE-1 trial demonstrated a 100% overall response rate (ORR) in patients with heavily pretreated relapsed/refractory multiple myeloma when they were treated with the anti-BCMA chimeric antigen receptor (CAR) T-cell therapy JNJ-4528.
“This study reports on the outcomes of patients treated with the LEGEND 2 BCMA CAR in the United States,” Andrew J. Cowan, MD, assistant professor of Medicine, Division of Medical Oncology, University of Washington School of Medicine; physician at Seattle Cancer Care Alliance; and assistant member in the Clinical Research Division, Fred Hutchinson Cancer Research Center, toldTargeted Oncology.“This CAR employs a murine BCMA that binds 2 separate sites. The early results are very encouraging. We see a 100% overall response rate and toxicities in keeping with CAR T cells, including cytokine release syndrome (CRS), predominantly grades 1/2.”
JNJ-4528 induced a 66% stringent complete response (CR) rate, 3% CR rate, 17% very good partial response (PR) rate, and 14% PR rate. In regard to safety of the drug, CRS occurred in 93% of patients across all grades, but only 2 patients reported CRS of grade 3 or higher. The most common grade 3 or greater hematologic adverse events (AEs) included neutropenia, thrombocytopenia, anemia, leukopenia, and lymphopenia.
“These results compete well with the bb2121 BCMA CAR, developed by BMS and Bluebird Bio. Further long-term follow-up is needed to know if the durability is better with this CAR construct, and, in my opinion, will be the critical factor determining which BCMA CAR will be most used in clinical practice,” Cowan concluded.
Encouraging Phase I Data for CC-93269 in Multiple Myeloma Reveals T-Cell Engager to Be Safe, Effective
In the phase I dose-escalation trial, promising safety profiling and encouraging signs of dose-dependent efficacy were observed in patients with heavily pretreated relapsed/refractory multiple myeloma with treatment of the human IgG1-based T-cell engaged, CC-93269, which binds BCMA and CD3 epsilon in a 2+1 format.
A 10 mg dose of CC-93269 induced an ORR for 88.9% of patients, which included a CR or stringent CR rate of 44.4%. Although a phase II dose has not yet been determined, the agent appears tolerable. Treatment-emergent adverse events (TRAEs) were reported in 96.7% of patients, in which 73.3% were grade 3 or greater. The most common hematologic TEAEs included neutropenia and anemia, while the most common non-hematologic TEAEs included CRS, infections and infestations, diarrhea, and vomiting.
“The preliminary safety findings are in keeping with what we’ve seen with T cell engagers and CAR Tincluding CRS in 76% of patients and 1 death due to grade 5 CRS in the higher dose cohort,” said Cowan. “The efficacy appears promising, particularly in the 9 patients at the highest dose level, where the ORR was 88.9%. The results are promising, but further long-term data and more patients treated are needed. Particularly in comparison with BCMA CAR T cells, these results look similar, but the durability of responses with BCMA T cell engagers in general at this early stage are an unanswered question.”
The phase I study (NCT03486067) continues to enroll patients for a total enrollment goal of 120. The estimated primary completion date is July 2021.
Nina Shah, MD
Phase III Study With Venetoclax Combo Identifies New Biomarker for Relapsed/Refractory Myeloma
According to the phase III BELLINI trial (NCT02755597) demonstrated translocation(t)(11;14) and high BCL2gene expression are predictive of response to treatment with the addition of venetoclax (Venclexta) to bortezomib (Velcade) plus dexamethasone in patients with relapsed/refractory multiple myeloma. Moreover, the triplet regimen induced promising response rates in this patient population.
Overall, the objective response rate (ORR) was 84% with the addition of venetoclax versus 70% with placebo. In the venetoclax arm, 61% of patients achieved a very good partial response (VGPR) or better, 29% achieved a complete response (CR) or better, and 13% of patients achieved minimal residual disease (MRD)-negativity versus 40%, 7%, and 1% in the placebo arm, respectively.
In the t(11;14) subgroup, venetoclax induced a 95% ORR, including a ≥VGPR of 75% of patients, a ≥CR of 55%, and MRD-negativity in 25% versus 47%, 27%, 7%, and 0% with placebo, respectively. The ORR in patients with high BCL2 was 88% with venetoclax, including a ≥VGPR of 76%, a ≥CR of 41%, and MRD-negativity in 18% versus 75%, 31%, 0%, and 0% in the placebo arm, respectively.
“This year we saw the first hints of biomarker-driven medicine, particularly for venetoclax in t(11:14) patients,” Nina Shah, MD, an associate professor of Medicine at the University of California, San Francisco Helen Diller Comprehensive Cancer Center, toldTargeted Oncology.“[BELLINI] confirmed that venetoclax is highly active in this sub-group of patients and should likely be considered as an option for patients with relapsed multiple myeloma with 1 to 3 prior lines of therapy.”
Patients With CLL Treated on the ELEVATE-TN Trial Experience Improved PFS With Acalabrutinib
Matthew S. Davids, MD, MMSc
In the phase III ELEVATE-TN trial, patients with treatment-naïve chronic lymphocytic leukemia (CLL) experienced a statistically significant improvement in progression-free survival (PFS) with acalabrutinib (Calquence) as a single agent or in combination with obinutuzumab (Gazyva) when compared with obinutuzumab plus chlorambucil.
At a median follow-up of 28.3 months, the combination of acalabrutinib plus obinutuzumab led to a 90% reduction in the risk of disease progression or death compared with obinutuzumab/chlorambucil. When used as monotherapy, acalabrutinib also showed a statistically significant benefit in PFS.
"This study represents the first phase III data for acalabrutinib in the frontline CLL treatment setting,” Matthew S. Davids, MD, MMSc, associate director of the Center for Chronic Lymphocytic Leukemia at the Dana-Farber Cancer Institute, toldTargeted Oncology. “The early efficacy and safety data look promising, and now that we have acalabrutinib FDA-approved for CLL in the United States, I think this robust data set provides confidence that this is another excellent option to discuss with our patients as they weigh the decision about initial therapy."
In November 2019, theFDA granted approval to acalabrutinibfor the treatment of patients with CLL or small lymphocytic lymphoma, partly based on data from the ELEVATE-TN.
Patients under 70 years old with CLL treated in the minimal residual disease (MRD)-cohort of the phase II CAPTIVATE trial had undetectable MRD (uMRD) rates of 75% and 72% in the peripheral blood and bone marrow, respectively, with the frontline combination of ibrutinib (Imbruvica) and venetoclax.
"We had recently seenpromising data published from a single center study of ibrutinib plus venetoclaxfor the frontline treatment of CLL. This presentation on the CAPTIVATE study reported on a much larger group of over 160 patients from a multicenter study of the same combination,” Davids said. “A high proportion of patients achieved uMRD in the bone marrow, and no new toxicity signals arose, suggesting that this is an important new regimen, although it will be important to develop comparative data between this approach and other effective frontline treatments."
The most common AEs associated with the combination treatment were primarily grades 1 or 2. Grade 3/4 AEs were most common in the first 3 cycles of treatment at 39%, then decreased to 15% during the last 3 to 4 cycles. Additionally, 57% of patients experienced TRAEs, and serious TRAEs occurred in 11% of the patients.
A fixed-duration of venetoclax plus obinutuzumab resulted in superior PFS and high rates of uMRD in patients with treatment-naïve CLL compared with chlorambucil plus obinutuzumab. Over 90% of patients experiencing durable responses 24 months after the end of therapy and beyond. Results of this study also confirm the prognostic value of MRD in targeted combination therapy in previously untreated CLL.
"This was an important update in this frontline study, as we now have over 3 years of follow-up on these patients treated with venetoclax plus obinutuzumab as a 1 year fixed-duration therapy,” Davids said. “Only 6% of patients progressed in year 3. After 1 year of therapy plus 2 years off therapy, 82% are still progression-free, suggesting that for the majority of patients treated with this regimen, there will be a durable benefit for a time-limited, chemotherapy-free approach."
Venetoclax plus obinutuzumab was associated with longer PFS than chlorambucil plus obinutuzumab at a median follow-up of 39.6 months. At 36 months, PFS was 82% in the venetoclax group versus 50% in the chlorambucil group. The venetoclax combination resulted in longer PFS in patients with mutated versus unmutated IGVH, and in patients with noTP53mutation or deletions versus those with TP53mutation or deletions. At the time of follow-up there was no difference between treatment groups for overall survival (OS), with 13% of patients in each group having an event.
"We presented data on our investigator-initiated trial of acalabrutinib, venetoclax, and obinutuzumab (AVO) for the first time at this meeting,” Davids toldTargeted Oncology.“Although the follow-up is early, about half of patients have already achieved uMRD in the bone marrow after only 4 cycles of venetoclax combination therapy. Rates of infusion-related reactions and typical toxicities associated with BTK inhibitors have been low.”
The open-label, single-arm phase II study demonstrated that frontline treatment with the AVO triplet regimen achieved uMRD in the bone marrow in 48% of patients after only 8 monthly cycles of therapy. After cycle 8, 16.7% of patients achieved a CR with undetectable MRD in the bone marrow. This rate was relatively unchanged (12.5%) after cycle 16, said Lampson, medical oncologist at Dana-Farber Cancer Institute. After a median follow-up of 11 cycles, the ORR was 97.3% after cycle 4, and 100% after both cycle 8 and cycle 16.
“We have expanded the study now to include a cohort of CLL patients who have high risk disease with deletion17por TP53mutation,” Davids concluded. “This AVO regimen is also now being studied in an ongoing phase 3 study, which if positive could allow this type of triplet novel agent approach to become a new standard of care option to consider for frontline CLL treatment."
According to findings from the phase III QUAZAR AML-001 trial, an extended median OS of 9.9 months was achieved with CC-486 maintenance compared with placebo for older patients with acute myeloid leukemia AML in first remission.
After a median follow-up of 41.2 months, the median OS with CC-486 was 24.7 months (95% CI, 18.7-30.5) compared with 14.8 months for placebo (95% CI, 11.7-17.6), representing a 31% reduction in the risk of death with the hypomethylating agent (HR, 0.69; 95% CI, 0.55-0.86; P = .0009). The median relapse-free survival (RFS) was 4.8 months with placebo compared with 10.3 months for CC-486
The safety profile was consistent with injectable azacitidine, with infrequent treatment discontinuation related to AEs. There were no treatment-related deaths. The most common all-grade AEs were gastrointestinal in nature, including nausea (65%), vomiting (60%), diarrhea (50%), and constipation (39%). The most common grade 3/4 AEs with CC-486 were neutropenia (41%), thrombocytopenia (23%), anemia (14%), diarrhea (5%), vomiting (3%), fatigue (3%), and nausea (3%).
Plans to submit a regularly application for CC-486 are in the works for in the first quarter of 2020.
Aaron T. Gerds, MD, MS
BET Inhibitor Combination Induces Spleen and Symptom Responses in Myelofibrosis
CPI-0610, an oral bromodomain and extra-terminal domain (BET) inhibitor, demonstrated spleen volume reduction, symptom improvement, and reduction in bone marrow fibrosis as monotherapy or in combination with the JAK inhibitor ruxolitinib (Jakafi) in patients with myelofibrosis (MF), according to data from the phase II MANIFEST trial.
“One of the abstracts that was very interesting was on a BET inhibitor in MF,” Aaron T. Gerds, MD, MS, of the Cleveland Clinic Taussig Cancer Institute, toldTargeted Oncology.“Pro-inflammatory cytokines play a central role in the pathogenesis and symptom burden in patients with MPNs, and this is trigged by JAK-STAT activation. However, JAK inhibition with medications like ruxolitinib don’t always lead to reduction in cytokines and amelioration of symptoms. Moreover, those who do derive benefit from JAK inhibition will eventually have a return of symptoms and splenomegaly while on treatment.”
Patients demonstrated splenic and symptomatic responses with the combination of CPI-0610 plus ruxolitinib as early as 12 weeks, at which time 80% of patients had a spleen volume reduction by 35% or greater, and 71.4% of the patients had a total symptom score improvement of 50% or greater. The combination was generally well tolerated, and no AEs led to study discontinuation.
“CPI-0610 is a great story of how to harness a complimentary pathway to JAK-STAT with a resulting increase in initial response rates and rescue lost responses,” Gerds said. “However, as all single-arm studies, it needs to be approached with cautious optimism, and randomized data are needed to confirm a benefit.”
In an interview withTargeted Oncology, John O. Mascarenhas, MD, a clinical investigator in myeloproliferative neoplasms, associate professor of medicine at the Icahn School of Medicine, and director of the Adult Leukemia Program at Mount Sinai in New York,discussed the findings from the MANIFEST trial and how CPI-0610 can impact patients with MFas a single-agent or in combination with the JAK inhibitor.
The addition of navitoclax, a small molecule inhibitor of BCLXL, BCL2, and BCLW, to ruxolitinib showed clinically meaningful spleen responses and improvements in symptoms as treatment of patients with primary or secondary MF who developed resistance to ruxolitinib in the first-line setting, according to findings from a single-arm study.
A spleen volume reduction of 35% or greater was achieved in 30% of the patients at week 24, while 65% of patients experienced a reduction in symptoms. Thirty-five percent of patients experienced a reduction in the total symptom score of 50% or greater. Additionally, 53% of patients had resolution of palpable splenomegaly.
Overall, 27% of patients discontinued navitoclax during the study due to AEs (9%), progressive disease (6%), and other causes (12%). Grade ≥3 AEs of any cause were experienced by 79% of patients receiving the combination. The most common grade ≥3 AEs were thrombocytopenia (44%), anemia (27%), diarrhea (6%), and vomiting (3%). Twenty-four percent of patients experienced a serious AE. There was 1 grade 5 case of pneumonia that was deemed unrelated to navitoclax.
The phase II study is still ongoing to further assess navitoclax alone or in combination with ruxolitinib for patients with MF (NCT03222609). Additionally, outside of the United States, an expanded access program is available to gain access to navitoclax (NCT03592576).
According to an updated analysis from the phase II ZUMA-1 trial, patients with refractory large B-cell lymphoma who were treated with axicabtagene ciloleucel (axi-cel; Yescarta) had a 3-year overall survival (OS) rate of 47%. The median duration of follow-up was 39.1 months.
The results that were reported at the 2019 ASH Annual Meeting demonstrated the CAR T-cell therapy induced a median OS of 25.8 months, with approximately 60% of patients having relapsed or progressed. At a previous 2-year analysis of the study, the objective response rate was 83% and the complete remission rate was 58%. The 2-year OS rate was 51% and the 2-year progression-free survival rate was 39%.
Previously, the FDA approved axi-cel in October 2017, as a treatment for adults with relapsed or refractory non-Hodgkin lymphoma, based on findings from the ZUMA-1 trial.
According to data from a single-center phase II study, the combination of obinutuzumab plus lenalidomide (Revlimid) resulted in early and very high CR rates in previously untreated patients with follicular lymphoma (FL). At a median follow-up of 25 months, the 2-year PFS was 96%.
With a median follow-up of 25 months, at the first response assessment 87% of patients experienced CRs, and the best CR rate was 94%. ORR was 94% at the first response assessment and 96% at the best response. No deaths were reported.
The most common grade 1/2 AEs included fatigue and gastrointestinal events. Common grade 3 and 4 AEs included neutropenia (17%, requiring growth factor support in 13%), rash (12%), fatigue (7%, all grade 3), and diarrhea (3%, all grade 3). There were 2 thromboembolic events, whereas 1 was life-threatening and the other was asymptomatic. There were 2 secondary malignancies, including non-invasive bladder cancer and non-melanoma skin cancer. Of the 18 patients who discontinued therapy, 13 were because of toxicity (14%), 3 because of progression (3%), and 2 for financial reasons (2%).
“There is still an unmet need, in my opinion, to develop highly effective but also well-tolerated frontline therapies that can challenge chemotherapy for the treatment of untreated follicular lymphoma,” Loretta J. Nastoupil, MD, Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, said during her presentation of the results at the 2019 ASH Annual Meeting.
Patients with relapsed/refractory FL showed durable responses with the combination of polatuzumab-vedotin (Polivy), obinutuzumab, and lenalidomide, according to results from the phase Ib/II trial. The 12-month PFS was 83%, and responses were reported by the the Lugano 2014 criteria and the modified Lugano 2014 criteria.
By the modified criteria, the investigator-assessed response rate was 83%, decreasing to 76% by independent review. CR was 61% and 63%, respectively. By the original Lugano criteria, 83% of patients had investigator-assessed objective responses and 76% by independent review. Complete response rates were 74% and 72%, respectively.
“These compelling findings support further investigation in a larger patient population as this novel triplet combination has a potential place as therapy for patients with relapsed and refractory follicular lymphoma,” Catherine Diefenbach, MD, director of the clinical lymphoma program at NYU Langone Health’s Perlmutter Cancer Center said during her presentation.
Out of 56 patients, 31 experienced grade 3/4 neutropenia (55%). The second most common AEs were thrombocytopenia (27%), infections (20%), anemia (14%), and febrile neutropenia (11%). AEs of special interest included tumor flare in 4 patients and myelodysplastic syndrome and lung malignancy in 1 patient each. Additionally, 77% of patients had AEs that led to dose interruption, 34% required dose reduction, and 30% discontinued due to AEs.
According to long-term follow-up data from a prospective trial, treatment with ibrutinib might prompt a decrease in PFS in patients with relapsed or refractory mantle cell lymphoma (MCL). Investigators reported updated pooled data from 3 clinical trialsSPARK, RAY, and PCYC-1104—of ibrutinib in relapsed/refractory MCL.
The median PFS was 12.5 months with ibrutinib as compared with an estimated 10.9 months with a patient’s more recent prior regimen. More than half of 370 patients had a longer PFS with ibrutinib than with the prior regimen, and 27% had a PFS ≥1 year longer than the prior regimens estimated PFS.
Patient age and number of prior lines of therapy did not significantly affect PFS with ibrutinib, although patients with a single prior line of therapy had the best PFS, along with those who attained a CR, according to the study results.
“Ibrutinib represents a significant advance in MCL and should be considered standard of care in second line, regardless of a patient’s initial response to frontline therapy,” study authors said.
Follow @TargetedOncfor the latest updates in oncology.
See more from the 2019 ASH Annual Meeting.