The novel coronavirus (COVID-19) spreading across the world represents a distinct challenge for all physicians, especially oncologists who commonly treat patients who have compromised immune systems. The spread of the virus was discussed by Scott Gottlieb, MD, during the keynote address at the 

At this point, the number of new confirmed cases of coronavirus infection seems to change every day, with more than 100,000 infections reported worldwide. When looking at epidemiology data, Gottlieb noted a distinct spike in reported respiratory illnesses across the United States. He partially credited this to additional hospital visits due to worry over the virus. However, given a lack of widespread testing, he added that it could also be from wider spread of the virus than estimated.

“I think we’re facing some difficult months ahead of this,” said Gottlieb. “Seeing what’s happening in some of the cities, there’s some speculation on just how bad this disease is. I think most of the modeling we’ve seen coming out, looking at South Korea, Italy, and certain parts of China, suggests the mortality rate will be about 1%, which is significantly more than the seasonal flu, which is about 0.1%.”

Gottlieb noted that each country seems to be handling the coronavirus outbreak differently. In China, he said there has been some success in containing the virus, but at significant social and human costs. On the opposite end of the spectrum, however, there seems to be very little effort on the part of Iran to slow the virus, allowing it to “burn through their population,” he said.

“We’re going to have to figure out what our American approach is to this and how we’re going to take more aggressive mitigation steps. We’re losing a pretty narrow window to step in,” Gottlieb said. “We really haven’t stepped in with the kind of mitigation step and social distancing in these hot spots that you’d want to see to break the chain of transmission. I think this week is going to be critical.”

Effective and widespread testing has represented another challenge facing the prevention of coronavirus spread. The initial step in the process, which was creation of a diagnostic by the Centers for Disease Control and Prevention (CDC), went as planned, he said; however, there was a shipment delay for reagents to public health labs, slowing down use of this test. Additionally, there was inadequate communication between the CDC and other testing organizations, such as LabCorp and Quest Diagnostics.

“In an ideal world, we would be doing what the Netherlands is doing. They’re testing their indeterminate cases of the flu. If someone shows up with the flu, gets swabbed, and shows up negative for the flu but still has a significant respiratory disease they’ll then get tested for the coronavirus,” said Gottlieb. “We announced that we’re going to start doing that in 5 cities, but that’s a small number.”

Each day, testing strategies continue to evolve and change, in response to the spread of the disease, with wider adoption of this testing strategy possible in the coming week. Additionally, several companies are now working to find treatments for the virus, including Gilead Sciences and Moderna.

Shifting topics in his keynote address, Gottlieb noted that innovation has been a mainstay in oncology for the past 2 decades, as new treatments have dramatically improved the long-term outcomes across several types of cancer. Innovation at the FDA has largely been driven by strategic changes made to endpoints, to allow for faster approval via surrogates. Looking solely for an improvement in overall survival has become steadily more difficult to achieve, he said, as treatments become more effective.

“The time required, and the large number of patients required, in the trial to demonstrate improvement or superiority over an otherwise effective regimen and in order to power that study it wouldn’t be practical, you couldn’t enroll it,” said Gottlieb. “We would potentially be denying effective drugs to patients who face life-threatening disease.”

Most of these changes were facilitated by a greater understanding of the biology that drives cancer, with a milestone approval seen with imatinib (Gleevec), which was the first targeted therapy approved by the agency. Other recent examples of innovation include immune checkpoint inhibitors and tumor agnostic approvals, he said.

Tissue-agnostic approvals were brought about following changes to the clinical trial designs, which was another key change at the FDA to foster greater innovation. FDA granted its first tissue-agnostic approval in 2017 for the PD-1 inhibitor pembrolizumab (Keytruda) for patients with unresectable or metastatic, microsatellite instability-high or mismatch repair deficient tumor tumors. This was followed by approvals for larotrectinib (Vitrakvi) and entrectinib (Rozlytrek) for patients with solid tumors harboring an NTRK fusion.

“We moved toward tissue-agnostic drug approvals, where you get the approval based on a molecular subtype rather than phenotype,” Gottlieb said. “You might be able to study multiple tumor types within one trial. The opportunity is forcing the agency to continue to evolve. It really was a palpable sense of real opportunity about what was happening.”

Hematology/Oncology (Cancer) Approvals & Safety Notifications. FDA Website. bit.ly/2EP6v4b. Accessed March 7, 2020.

View more from the 2020 Miami Breast Cancer Conference

Articles

The novel coronavirus spreading across the world represents a distinct challenge for all physicians, especially oncologists who commonly treat patients who have compromised immune systems.

Gottlieb Addresses Coronavirus, Innovation in Keynote Address

Gene profiling assays can accurately and reproducibly assist decision making for patients with hormone receptor (HR)-positive breast cancer, with the ultimate goal of improving outcomes or avoiding toxicity, according to a presentation at the 

“This is an area that touches all of the specialties of breast cancer treatment,” said Tripathy, professor and chair, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center. “In the last 10 to 20 years, we’ve gotten more sophisticated tools, such as gene profiling, to further build out the subsets. We’re focusing on the benefits of chemotherapy, and there are many established prognostic factors that we all commonly use."

Table. Short- and Long-Term Effects of Treatment (Click to Enlarge)

National Comprehensive Cancer Network (NCCN) treatment recommendations provide guidance on the optimal test to utilized, based on the level of clinical evidence demonstrated in prospective validation, registry, population-based, and clinical trials. Based on findings from TAILORx and MINDACT trials, respectively, category 1 recommendations are given for Oncotype Dx for node-negative, HR-positive/HER2-negative disease and MammaPrint for node-negative to 1 to 3 node-positive breast cancer. Of these 2 tests, Oncotype DX is listed as preferred by the guideline and is the only to provide predictive value.

“There are many other assays that may be performed just as well but they aren’t tied to a randomized clinical trial,” Tripathy said.

 included more than 10,000 patients with HR-positive, HER2-negative, axillary node-negative breast cancer. Patients were stratified by risk using the Oncotype DX assay, with 9719 having follow-up information available for analysis. Overall, 69% (n = 6711) had an intermediate recurrence score of 11 to 25; 17% (n = 1619) had a score of 10 or lower; and, 14% (n = 1389) had a score of 26 or higher.

Those in the low-risk group received endocrine therapy alone while patients in the high-risk group were treated with the combination of chemotherapy and endocrine therapy. Patients in the intermediate group were randomized to receive either endocrine therapy alone (n = 3399) or chemotherapy plus endocrine therapy (n = 3312). Endocrine therapy most commonly consisted of an aromatase inhibitor for postmenopausal women and tamoxifen alone or with an aromatase inhibitor for premenopausal women.

After a median of 7.5 years of follow-up, endocrine therapy alone was noninferior to chemotherapy plus endocrine therapy for invasive disease-free survival (DFS) in the intermediate group (hazard ratio, 1.08; 95% CI, 0.94-1.24; 

 = .26). Moreover, freedom from recurrence at a distant site was similar between the two groups (hazard ratio, 1.10; 95% CI, 0.85-1.41; 

For those >50 years, there was no additional benefit observed with the addition of chemotherapy for patients with risk scores from 0 to 25. In those 50 years of age or younger, however, there was a benefit for adding chemotherapy in the intermediate risk group, although the rationale behind this is still unclear, Tripathy noted.

In this age group in those with a recurrence score of 16 to 20, there was a 1.6% different between for 9-year distant recurrence. In the 21 to 25 recurrence score group, 6.5% more patients recurred at 9 years in the endocrine alone arm compared with the chemotherapy plus endocrine arm (86.9% vs 93.4% freedom from recurrence rates).

“This might be explained by the fact that women in the younger age group can undergo menopause with chemotherapy, and it might be that benefit and not chemotherapy that is helping them,” said Tripathy. “This is still controversial to see whether we should be using chemotherapy or ovarian suppression instead. This is still a dilemma.”

 helped establish the 70-gene MammaPrint test as a tool for determining whether chemotherapy could be withheld. For this study, patients were stratified based on their clinical and genetic risk. Those with low risk by both measures (n = 2745) did not receive chemotherapy while those with high-risk for both were treated with chemotherapy (n = 1806). A second group with clinical-low but genetic-high (n = 592) risk or clinical-high but genetic-low (n = 1550) risk were randomized to receive chemotherapy or no chemotherapy.

In those with clinical-low/genetic-high risk, the 5-year distant metastasis-free survival (MFS) was similar regardless of treatment type, illustrating an ability to avoid chemotherapy. In the chemotherapy arm, the 5-year distant MFS rate was 95.8% compared with 95.0% in the chemotherapy-free arm (hazard ratio, 1.17; 95% CI, 0.59-2.28; 

 = .657). For those with clinical-high/genetic-low risk, the 5-year distant MFS was 95.9% in the chemotherapy group versus 94.4% in the chemotherapy-free arm (hazard ratio, 0.78; 95% CI, 0.50-1.21; 

“With this assay, you can really take the higher-risk group, primarily the node positive ones, and, if they have a low recurrence score, you might surmise that based on these data they may not benefit from chemotherapy,” said Tripathy. “This is what is reflected in the ASCO guidelines.”

The ASCO guidelines4 note that clinical utility for MammaPrint is only indicated in patients with high clinical risk, for both those with node-negative and node-positive cancers. ASCO also updated its guidelines, following the presentation of the TAILORx results. In these guidelines, chemotherapy is listed as having little to no benefit for those age >50 years with an Oncotype DX score of <26 or those with ≤50 years with a score of <16.

For the NCCN guidelines there are 5 gene tests listed for invasive breast cancer, specifically Oncotype DX, MammaPrint, Breast Cancer Index (BCI), Prosigna (PAM 50), and Endopredict.

 Each of these assays examines different molecular characteristics and varying quantities of genes. The Oncotype DX test uses the expression of 21 genes, MammaPrint examines 70 genes, Prosigna is a 50 gene profile, BCI examines 7 key genes and ratios, and EndoPredict is a 12-gene panel. Additional assays continue to be assessed and will be added to the guidelines once they’re clinically validated, Tripathy noted.

Breast Cancer, version 2.2020. NCCN website. www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed March 6, 202.

Sparano JA, Gray RJ, Makower DF, et al. Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer. 

Cardoso F, van't Veer LJ, Bogaerts J, et al. 70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer. 

Andre F, Ismaila N, Henry NL, et al. Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: ASCO clinical practice guideline update—integration of results from TAILORx. 

Tailoring therapy can help avoid many of the short- and long-term side effects associated with various treatments (

). The main prognostic criteria are tumor size, nodal status, tumor grade, and molecule profile, Tripathy noted. Several predictive factors also exist, which should be considered for each patient. In addition to HR status and HER2 expression levels, tumor grade and gene expression profiles can be used to determine the appropriateness of chemotherapy.

Gene profiling assays can accurately and reproducibly assist decision making for patients with hormone receptor-positive breast cancer, with the ultimate goal of improving outcomes or avoiding toxicity.

Gene Profiling Essential Tool for Treatment Tailoring

The anti-BCMA CAR T cell therapy bb21217 demonstrated high very good partial response (VGPR) or better rates in patients with heavily pretreated relapsed/refractory multiple myeloma, with minimal residual disease (MRD) negativity seen in most patients with confirmed responses, according to updated results from the phase I CRB-402 study presented at the 2019 ASH Annual Meeting.

The longest follow-up from the study (median 17.6 months) was available for patients receiving a 150 x 10

 dose of bb21217, which was the lowest dose explored in the study. In this cohort, the complete remission (CR) or stringent CR (sCR) rate was 33% and the VGPR rate was 50%, for an objective response rate (ORR) of 83%. All patients in this group were MRD-negative and the median duration of response was 11.1 months.

 dose cohort, the median duration of response is promising at 11.1 months. In the higher dose cohorts, follow up is short but there are no confirmed responders who have progressed," Jesus G. Berdeja, MD, from the Sarah cannon Research Institute, said during a presentation of the results. "The safety profile of bb21217 in this phase I study of relapsed/refractory multiple myeloma remains consistent with known toxicities of CAR T-cell therapies."

As part of the bb21217 manufacturing process, the CAR T-cell therapy bb2121 is cultured with the PI3 kinase inhibitor bb007 to enrich for T cells with a memory-like phenotype. In preclinical experiments, bb2121 and bb21217 both eliminated an initial tumor in mice; however, when rechallenged with a second tumor in the same mouse, only bb21217 prevented the tumor from growing without retreatment. Additionally, bb21217 also showed higher levels of CCR7 and CD27 compared with bb2121, suggesting higher levels of memory-like T cells, and bb21217 had lower levels of CD57, a marker of T cell exhaustion.

In the phase I study of bb21217, patients were treated with 150 x 10

(n = 6) CAR+ T cells in an initial dose escalation stage. An expansion cohort was opened to further explore the 300 x 10

 doses (n = 6), with the latter selected for further investigation. Lymphodepleting chemotherapy was given with fludarabine at 30 mg/m

 on days -5, -4, and -3 prior to infusion.

Across the study, 41 patients underwent leukapheresis, with 1 withdrawing and 2 receiving the infusion after the data cutoff. There was a 100% manufacturing success rate, although 3 patients were required to undergo remanufacturing prior to treatment. Patients were allowed to receive bridging therapy during the manufacturing process.

"[Time from leukapheresis to infusion] was about 4 to 5 weeks, which is standard for most of these targeted CAR T cells," said Berdeja. "Bridging therapy was left up to the individual investigator but I suspect that about half if not two-thirds of patients had bridging therapy."

The median age of patients enrolled in the study was 62 years (range, 33-74), and the median time since diagnosis was 5.5 years. Most patients had an ECOG performance status of 1 (63%) and an ISS stage of I (29%). A third of patients (34%) had high-risk cytogenetics and the median number of prior regimens received was 6 (range, 3-17). Ninety-five percent of patients had received prior proteasome inhibitors, IMiDs, and an anti-CD38 antibody. Eighty-two percent of patients had received 1 or more prior autologous stem cell transplants.

The median follow-up for patients in the 300 x 10

 doses was 4.0 and 3.3 months, respectively. At these early assessments, the ORR in the 300 x 10

 dose arm was 43%, which included a VGPR rate of 29% and a partial response (PR) rate of 14%. However, Berdeja warned that with the short follow up, these numbers were misleading, as some patients were not included in the analysis.

"Many of these patients had not reached 2 assessments to have a confirmed response and were left off the overall response for these percentages, especially for the 450 group," he said. "As is expected with CAR T cells, the responses will deepen over time."

 dose, the ORR was 57% and was composed of a PR rate of 14%, a VGPR rate of 29%, and an sCR/CR rate of 14%. None of the responding patients had progressed at the time of the data cutoff in September 2019.

The MRD-negative rate was 94% across the full study, with just 1 patient not achieving negative status at the assessment in the 300 x 10

 dose arm. At 6 months, CAR T cells continued to be detectable for 8 of 10 patients (80%). Although the numbers were small, at month 12 bb21217 was detectable in 2 of 4 patients (50%). Of the 2 patients with 18 months of follow up, both still had detectable levels of bb21217 (100%).

"bb21217 drug product is enriched for memory-like T cells, which are associated with robust CAR T cell expansion and less disease progression at month 6," said Berdeja. “Long-term CAR T-cell persistence was observed in 8 of 10 evaluable patients at month 6 and 2 of 2 at month 18.”

All-grade cytokine release syndrome (CRS) occurred in 66% of patients, most of which was grade 1 or 2 in severity; however, 1 patient had a grade 5 CRS event at the 450 x 10

 dose. The median time to onset of CRS was 3 days and the median duration of CRS was 4 days. Neurotoxicity occurred in 24% of patients. There were 2 grade 3 events and 1 grade 4 event, with the remainder being grade 1 or 2. The median time to neurotoxicity onset was 7 days.

Grade 3/4 treatment-emergent adverse events (AEs) included neutropenia (82%), leukopenia (55%), thrombocytopenia (55%), anemia (50%), lymphopenia (34%), hypophosphatemia (21%), infection (18%), hyponatremia (13%), and febrile neutropenia (11%). Half of patients had a serious AE (50%), and 95% had at least 1 grade 3/4 AE.

The expansion arm of the CRB-402 study continues to enroll participants for the 450 x 10

 dose of bb21217. The planned enrollment for the study is 74 patients (NCT03274219).

Berdeja JG, Alsina M, Shah N, et al. Updated results from an ongoing phase 1 clinical study of bb21217 anti-BCMA CAR T cell therapy. Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 927. bit.ly/35bET49.

The CAR T cell therapy bb21217 demonstrated high very good partial response or better rates in patients with heavily pretreated relapsed/refractory multiple myeloma.

Updated bb21217 Data Continue to Impress in Multiple Myeloma

The addition of navitoclax to ruxolitinib (Jakafi) showed clinically meaningful spleen responses and improvements in symptoms for patients with primary or secondary myelofibrosis, following the development of resistance to frontline ruxolitinib, according to findings from a phase II study presented at the 2019 ASH Annual Meeting.

In the single-arm study, spleen volume response of ≥35% (SVR35) was achieved by 30% of patients at week 24. Additionally, 53% of patients had resolution of palpable splenomegaly. Sixty-five percent of patients experienced a reduction in symptoms, and 35% of patients experienced a ≥50% reduction in total symptom score (TSS).

"With the addition of navitoclax to ruxolitinib, we were able to observe that there are meaningful spleen responses and improvements in symptom scores," Jacqueline S. Garcia, MD, Department of Medical Oncology, Dana-Farber Cancer Institute, said during a presentation of the findings. "The addition of navitoclax overcomes resistance in patients with uncontrolled myelofibrosis, despite prior prolonged ruxolitinib exposure."

Navitoclax is a small molecule inhibitor of BCLXL, BCL2, and BCLW, which has shown signs of activity in myeloproliferative neoplasm cell lines, including in myelofibrosis. In preclinical models, the combination of JAK2, BCLXL, and BCL2 inhibition was able to synergistically overcome JAK2 mutations and resistance to JAK2 inhibitors.  

The phase II study enrolled 34 patients with primary myelofibrosis (n = 16), post-essential thrombocythemia myelofibrosis (n = 5), and post-polycythemia vera myelofibrosis (n = 13). All patients had received ruxolitinib for ≥12 weeks prior to first dose of navitoclax, with no wash out period prior to the start of the trial. The dose of navitoclax was escalated from 50 mg daily to 300 mg daily over the course of the study. 

Of those available for baseline testing, more than half had high molecular risk (52%). The most common mutations identified were JAK2 (79%) and CALR (21%). Overall, 47% of patients at high-risk had 2 or more mutations. The duration of prior ruxolitinib therapy was 21 months (range, 4-71) and the baseline spleen volume was 1665 cm

The best achieved SVR35 was 43% for the combination. Additionally, 25% of patients saw a reduction in bone marrow fibrosis compared with baseline. There was a 1 grade reduction for 13% of patients and a 2 grade improvement for 13% of patients.

The mean white blood cell count at week 24 was 25.8 x 10

/L. Two patients entered the study with transplant dependence, with 1 becoming transplant independent following the addition of navitoclax. Seven patients entered the study receiving ≥1 unit of packed red blood cells within the past 12 weeks. Of these patients, 57% were transplant-free for ≥12 weeks following treatment with the combination. Platelet counts stabilized during the study, going from 232 x 10

"Although very early transient thrombocytopenia was observed immediately after dosing, as expected, it was manageable with a slow weekly dosing ramp up," said Garcia. "The time frame of the 8-week nadir is similar to what we initially observed with ruxolitinib alone."

The median duration of navitoclax treatment was 330 days, and 68% were able to achieve the maximum tolerated dose of 300 mg. Most patients entered the trial on ruxolitinib doses >10 mg twice daily (BID) but most were able to reduce their dose to 10 mg BID during the study (88%).

A quarter of patients discontinued navitoclax during the study (27%), due to adverse events (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%). Eight patients experienced a serious AE (24%). 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 myelofibrosis (NCT03222609). Additionally, outside of the United States, an expanded access program is available to gain access to navitoclax (NCT03592576).

Harrison CN, Garcia JS, Mesa JA, et al. Results from a phase 2 study of navitoclax in combination with ruxolitinib in patients with primary or secondary myelofibrosis. Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 671. bit.ly/343YuBX.

Navitoclax plus ruxolitinib (Jakafi) showed clinically meaningful spleen responses and improvements in symptoms for patients with primary or secondary myelofibrosis, following the development of resistance to frontline ruxolitinib.

Navitoclax Overcomes Ruxolitinib Resistance for Myelofibrosis

Maintenance treatment with CC-486, an oral formulation of azacitidine, extended median overall survival (OS) by 9.9 months compared with placebo for older patients with acute myeloid leukemia (AML) in first remission, according to findings from the phase III QUAZAR AML-001 trial presented at the 2019 ASH Annual Meeting.

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; 

 = .0009). The median relapse-free survival (RFS) was 4.8 months with placebo compared with 10.3 months for CC-486 (HR, 0.65; 95% CI, 0.52-0.81; 

"Based on the positive results of this landmark trial, we hope that maintenance therapy with CC-486 represents a new potential therapeutic standard for patients aged 55 or older with AML in first remission," Andrew H. Wei, MBBS, PhD, from the Alfred Hospital and Monash University, Melbourne, Australia, said during a presentation of the results. "Maintenance studies have been undertaken for the last 30 years and to date no particular therapy has been shown to improve overall survival."

CC-486 has a distinct pharmacokinetic and pharmacodynamic profile from injected azacitidine. Earlier studies have shown the agent to be tolerable with efficacious, even in patients who have progressed on prior azacitidine injections. The oral dosing of the drug is felt to provide better drug exposure, in addition to superior patient convenience, which potentially prolongs therapeutic activity, Wei said.

In the phase III trial, 472 patients were enrolled within 4 months of complete remission (CR) or CR with incomplete hematologic recovery (CRi). Patients were evenly randomized to receive therapy with daily CC-486 (n = 238) or placebo (n = 234). CC-486 was administered daily for 14 days followed by 14 days off therapy. If a CR/CRi was not maintained, CC-486 dose could be escalated to 21 days on drug with 7 days of rest.

The median age of patients was 68 years, with over two-thirds ≥65 years. The most common ECOG performance scores were 0 (47% to 49%) and 1 (42% to 45%). Most patients had de novo AML (approximately 90%) and most had intermediate cytogenetic risk (approximately 86%).

In the CC-486 groups, the best responses to prior therapy consisted of CR for 79% of patients and CRi for 21%. In the placebo arm, the best responses were CR for 84% of patients and CRi for 16%. Across both groups, approximately one-fifth of patients had not received consolidation therapy prior to study entry and approximately half of patients tested negative for minimal residual disease.

At 1 year, 47% of patients were free of relapse in the CC-486 arm compared with 29% in the placebo group. Benefits in both RFS and OS were seen across key prognostic AML subgroups, Wei said.

The median treatment duration was 12 cycles with CC-486 compared with 6 in the placebo group, which speaks to the tolerability of the agent, Wei said. "One measure of safety is the number of cycles the patient can tolerate," he said. "Some patients in the CC-486 arm received up to 80 cycles of treatment.

The safety profile was consistent with injectable azacitidine, with infrequent treatment discontinuation related to adverse events (AEs). There were no treatment-related deaths. The most common all-grade AEs with CC-486 were gastrointestinal in nature, including nausea (65%), vomiting (60%), diarrhea (50%), and constipation (39%). The most common grade 3/4 AEs in the CC-486 and placebo groups, respectively, were neutropenia (41% vs 24%), thrombocytopenia (23% vs 22%), anemia (14% vs 13%), diarrhea (5% vs 1%), vomiting (3% vs 0%), fatigue (3% vs 1%), and nausea (3% vs 0.4%).

"Although the gastrointestinal events seem high here, it was because this was a placebo-controlled study, so we did not know which treatment patients were receiving initially. When people get azacitidine-like therapy, they do get gastrointestinal side effects," said Wei. "In subsequent cycles, patients were put on prophylactic therapy, so these events were significantly reduced beyond cycle 2."

Topline results from the QUAZAR study were announced in September by the manufacturer of the drug, Celgene. In this statement, the company announced plans to submit a regularly application for CC-486 in the first quarter of 2020.

Wei AH, D&#1255;hner H, Pocock C, et al. The QUAZAR AML-001 Maintenance Trial: Results of a Phase III International, Randomized, Double-Blind, Placebo-Controlled Study of CC-486 in Patients with Acute Myeloid Leukemia (AML) in First Remission. Presented at: 2019 ASH Annual Meeting, Orlando, FL, December 7-10, 2019. Abstract LBA3.

Maintenance treatment with CC-486, an oral formulation of azacitidine, extended median overall survival by 9.9 months compared with placebo for older patients with acute myeloid leukemia in first remission.

Maintenance CC-486 Improves Survival for Older Patients With AML

Treatment with the anti-CD19 CAR T-cell therapy KTE-X19 elicited a complete remission (CR) rate of 67% and an objective response rate (ORR) of 93% for patients with relapsed/refractory mantle cell lymphoma (MCL), according to findings from the phase II ZUMA-2 study presented at the 2019 ASH Annual Meeting.

The median follow-up at the analysis was 12.3 months (range, 7.0-32.3), with 47% of patients having followed for ≥24 months. Forty percent of patients who initially had a partial remission (PR) or stable disease transitioned to CRs, with a median time CR of 3 months (range, 0.9-9.3). There were no cases of grade 5 cytokine release syndrome (CRS) or neurotoxicity.

Based on findings from the ZUMA-2 trial, Kite and Gilead plan to submit a biologics license application to the FDA within the next few weeks for KTE-X19 in relapsed/refractory MCL. A marketing authorization application will also be submitted to the European Medicines Agency (EMA) in the first quarter of 2020.

"KTE-X19, in a single infusion, demonstrates high rates of durable responses in relapsed/refractory mantle cell lymphoma," Michael L. Wang, MD, the University of Texas MD Anderson Cancer Center, said during a presentation of the results. "The 93% overall response rate, which includes a 67% CR rate, is the highest reported rate of disease response in patients with prior BTK inhibitor failure."

KTE-X19 consists of an anti-CD19 single-chain variable fragment with a CD3 zeta T cell activation domain and a CD28 signaling domain. During the manufacturing process, circulating tumor cells are separated from autologous immune cells, which differentiates KTE-X19 from axicabtagene ciloleucel (Yescarta), Wang noted.

Overall, 74 patients were enrolled and underwent leukapheresis in the study, with 5 patients not receiving the therapy due to manufacturing failures (n = 3) or death from progressive disease (n = 2). Overall, 69 patients went on to receive conditioning chemotherapy with 68 received KTE-X19. The primary efficacy analysis presented at ASH was conducted on the first 60 patients enrolled in the study. Overall, KTE-X19 was effectively manufactured for 96% of patients and administered to 92%. The median time from leukapheresis to delivery of KTE-X19 was 16 days.

"The efficacy, reliable and rapid manufacturing, and manageable toxicities identify an important and promising role for KTE-X19 in treating patients with relapsed/refractory mantle cell lymphoma who have an urgent unmet medical need," said Wang.

During the manufacturing process, patients in the study were allowed to receive bridging therapy for progressive disease at the investigator’s discretion. This could include ibrutinib, acalabrutinib, or dexamethasone but not chemotherapy. Beginning 5 days prior to T cell infusion, patients received 3 consecutive days of conditioning chemotherapy with fludarabine at 30 mg/m2 plus cyclophosphamide at 500 mg/m2. KTE-X19 was administered at 2 x 106 cells as a single infusion.

The median age of patients enrolled in the study was 65 years, with 57% aged ≥65 years. Most patients had stave IV disease (85%) and 56% were intermediate or high-risk. The Ki-67 proliferation index was ≥50% in 69% of patients and 17% had TP53 mutations. Bone marrow involvement was found in 54% of patients, and 56% had extranodal disease. The most common morphologies were classical (59%), blastoid (25%), and pleomorphic (6%).

Prior to study entry, patients had received a median of 3 prior therapies, with that majority having 3 or more treatments (81%). Almost all patients had received prior anthracycline or bendamustine and 100% of patients had received a prior anti-CD20 antibody. BTK inhibitors had been received by 100% of patients prior to study entry. Thirty-seven percent of patients received bridging therapy, most commonly with ibrutinib (21%). Of those who received bridging therapy, most had higher disease burden prior to infusion of the CAR T cells compared with baseline (92%).

"Bridging therapy was not intended to be curative, but simply to keep the lymphoma stable during manufacturing. The majority had increased tumor load instead of decreased tumor load," Wang said.

At the time of the analysis, the median duration of response had not yet been reached. Of those reaching a CR, 78% remained in remission at the time of the analysis. For the first 28 patients treated on the trial, the median follow-up was 27.0 months. In these patients, 43% of responders remained in remission, suggesting high durability of response with a plateau in the curve.

The median progression-free survival (PFS) was not yet reached. The 12-month PFS rate was 61%, with a tail on the curve (95% CI, 45%-74%). Additionally, the median overall survival (OS) was also not reached, with a 12-month OS rate of 83% (95% CI, 71%-91%).

"I have been treating mantle cell lymphoma for 20 years, and every time I see a plateau in the curve, I get very excited. But the follow-up is very short. We are still cautiously optimistic," said Wang.

As a single arm study, Wang cited historical numbers for context. Overall, a typical ORR in patients with MCL who progress on BTK inhibition is 25% to 42%, he said. Additionally, few patients in this setting go on to receive potentially curative allogeneic stem cell transplant. The median OS for these patients is between 6 and 10 months. For the ZUMA-2 trial, at the 12.3-month analysis, the low end of the 95% CI for OS with KTE-X19 was 24 months.

The most frequent treatment-emergent adverse event (TEAEs) of any grade were pyrexia (94%), neutropenia (87%), thrombocytopenia (74%), anemia (68%), and hypotension (51%). Grade 4 TEAEs included neutropenia (69%), thrombocytopenia (35%), hypoxia (9%), and hypotension (3%). There were 2 grade 5 AEs: the first was pneumonia related to the conditioning therapy and the second was staphylococcal bacteremia due to post-conditioning therapy and the CAR T cell infusion.

All grade CRS occurred in 91% of patients, which was grade ≥3 in severity for 15% of patients. The majority of pyrexia, hypotension, and hypoxia events seen in the study were related to CRS. Management for CRS included tocilizumab (59%) or corticosteroids (22%). The median time to onset was 2 days and the median duration was 11 days. All events resolved.

All grade neurotoxicity was experienced by 63% of patients treated with KTE-X19, with 31% having a grade ≥3 event. The most common symptoms were tremor (35%), encephalopathy (31%), and confusion (21%). This AE was managed with tocilizumab (26%) and corticosteroids (38%) and the median time to onset was 7 days with a median duration of 12 days.

There was one case of grade 4 cerebral edema in the study that was confirmed using MRI of the brain. Following intubation, this patient was treated with aggressive therapy, including tocilizumab, siltuximab, high-dose steroids, intrathecal Ara C plus dexamethasone, mannitol, ventriculostomy, and IV rabbit anti-thymocyte globulin (ATG). The neurotoxicity fully resolved for this individual and the CR had remained ongoing for 24 months at the data cutoff.

"This is the first reported use of ATG in treating CAR T cell-related toxicities," said Wang. Anecdotally, he added that he had seen this patient recently, and that they remained in CR. Making the duration of response 30+ months.

In addition to the upcoming BLA submission, KTE-X19 has received a breakthrough therapy designation from the FDA and a prime medicines (PRIME) designation from the EMA, both based on findings from the ZUMA-2 trial.

Wang ML, Munoz J, Goy A, et al. KTE-X19, an Anti-CD19 Chimeric Antigen Receptor (CAR) T Cell Therapy, in Patients (Pts) With Relapsed/Refractory (R/R) Mantle Cell Lymphoma (MCL): Results of the Phase 2 ZUMA-2 Study. Presented at: 2019 ASH Annual Meeting, Orlando, FL, December 7-10, 2019. Abstract 754.

Treatment with the anti-CD19 CAR T-cell therapy KTE-X19 elicited a complete remission rate of 67% and an objective response rate of 93% for patients with relapsed/refractory mantle cell lymphoma.

KTE-X19 Shows High CR Rates for MCL, FDA Submission Planned

The BET inhibitor CPI-0610 demonstrated promising spleen volume responses (SVR) and a meaningful reduction in total symptom score (TSS) as monotherapy and when added to ongoing treatment with ruxolitinib (Jakafi) for patients with refractory or intolerant advanced myelofibrosis, according to updated findings from the phase II MANIFEST trial presented at the 2019 ASH Annual Meeting.

For CPI-0610 added on to ongoing treatment with ruxolitinib, there was a 24.9% median reduction in spleen volume at 24 weeks and a 58.8% median improvement in TSS for transfusion dependent (TD) patients with myelofibrosis. Additionally, 43% of patients converted from being TD to transfusion independent (TI) following treatment with the combination. Promising improvements in TSS and SVR were also seen for CPI-0610 monotherapy.

"CPl-0610 as monotherapy or add-on to ruxolitinib in relapsed/refractory population demonstrated antitumor activity, as evidenced by spleen and symptom improvements, along with improvements in hemoglobin and bone marrow fibrosis," John Mascarenhas, MD, Tisch Cancer Institute, Division of Hematology/Medical Oncology, Icahn School of Medicine at Mount Sinai, said during a presentation of the results. "Among evaluable patients who were transfusion dependent on ruxolitinib, 6 of 14 patients converted to transfusion independence after the addition of CPl-0610 in the study."

CPI-0610 is thought to reduce and suppress the differentiation of myeloid cells into megakaryocytes in the bone marrow, potentially leading to disease modification for patients with myelofibrosis. In addition to this mechanism, the inhibition of BET proteins further halts the creation of pro-inflammatory cytokines, such as IL-8, TGFβ, and NFκB.

The MANIFEST trial included multiple treatment arms, each looking at cohorts of TD and TI patients. Arm 1 of the study examined single-agent CPI-0610 for patients no longer on ruxolitinib (n = 36). In arm 2 of the study, CPI-0610 was added to ruxolitinib for patients already receiving the JAK/STAT inhibitor for at least 6 months (n = 54). Arm 1 of the study included cohort 1A, in which patients were TD. Cohort 1B within this same group included those who were TI. In arm 2, patients included in cohort 2A of this group were TD and cohort 2B were TI.

In arm 2 looking at the combination of CPI-0610 and ruxolitinib, an SVR with at least 35% reduction in spleen size (SVR35) at week 24 was experienced by 25% of TD patients. Additionally, a TSS reduction of ≥50% (TSS50) at week 24 was experienced by 54% of TD patients. Seventy-five percent of patients noted an improvement in overall status by patient global impression of change (PGIC) scores. Sixty-one percent of patients said their status was much or very much improved. 

In TI patients treated with the combination, the SVR35 rate was 0 and the TSS ≥50% response was 38% at 24 weeks. In this group, there was a 69% improvement in PGIC score, with 46% of patients saying their overall status was much or very much improved.

In TD patients in arm 1, which looked at CPI-0610 monotherapy, the SVR35 was 0 and there was a median reduction in spleen size of 3.2% in TD patients. TSS ≥50% was 0 with the single agent, with a mean reduction from baseline of 18.4%. The PGIC score improved by 50%. In TI patients in arm 1, the SVR35 was 0 and the median change in spleen reduction was 26%. TSS ≥50% occurred in 60% of patients, with a median reduction of 53.5%. At 24 weeks, there was a 100% improvement in PGIC scores, with more than half of patients saying they were much improved (57%).

In the CPI-0610 monotherapy and add-on groups, respectively, 55% and 13% of patients had improvements of ≥1.5 g/dL in hemoglobin counts. Bone marrow fibrosis was improved from baseline to subsequent bone marrow biopsy for 22.2% and 43.5% of patients in the monotherapy and add-on groups, respectively. Both hemoglobin and bone marrow fibrosis improvements were seen in 22.2% and 17.4% of patients, in the single-agent and add-on arms, respectively.

Of those who transitioned from TD to TI, 36.4% in the add-on arm had bone marrow improvement. A 1 grade improvement in bone marrow fibrosis was seen in 38% of patients analyzed, with most of these occurring within 6 months of treatment (83%).

Across both groups, 83.3% of patients continued on the study at the time of the analysis. The primary reason for discontinuation was progressive disease (5.6%) or death (5.6%). The median treatment duration was 16.2 weeks, and 41.1% of patients have been on treatment for 24 weeks or longer.

The most common all-grade, all-cause adverse events (AEs) were diarrhea (32.2%), thrombocytopenia (23.3%), nausea (22.2%), cough (16.7%), vomiting (14.4%), fatigue (14.4%), and upper respiratory tract infection (14.4%). Non-hematologic AEs were primary grade 1/2 in severity, Mascarenhas noted.

The most common grade ≥3 AEs were thrombocytopenia (10%), anemia (6.7%), diarrhea (4.4%), and fatigue (3.3%). None of the grade ≥3 cases of thrombocytopenia were deemed serious, Mascarenhas noted. Across the 90 patients enrolled in the study, 8 experienced a grade 4 AE (8.9%). There were 3 grade 5 events (3.3%), which were not considered related to CPI-0610. These events all occurred in arm 2 of the study.

"CPl-0610 as monotherapy and as add-on was generally well tolerated. Thrombocytopenia was observed and asymptomatic. It was generally reversible and manageable and there were no additional unanticipated safety concerns observed," said Mascarenhas.

Based on findings from the first arms of the study, cohort 2A was expanded to enroll an additional 60 patients for the combination of CPl-0610 and ruxolitinib. Additionally, arm 3 of the study, which was not presented as part of this presentation, is looking at the combination of CPI-0610 with ruxolitinib in untreated patients with myelofibrosis.

 the SVR35 response rate was 80% at 12 weeks. The median change from baseline in spleen size was 49.7%. This response was seen in a high-risk population, including in those with DIPSS intermediate-2 or higher disease (86.7% response) and those with HMR-positive disease (53.3% response).

Based on these preliminary findings, cohort 3 of the study is being expanded to enroll up to 101 patients (NCT02158858).

Mascarenhas J, Kremyanskaya M, Hoffman R, et al. MANIFEST, a phase 2 study of CPI-0610, a Bromodomain and Extraterminal Domain inhibitor (BETi), as monotherapy or “add-on” to ruxolitinib, in patients with refractory or intolerant advanced myelofibrosis. Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 670. bit.ly/2YyH3IH.

Harrison CN, Patriarca A, Mascarenhas J, et al. Preliminary report of MANIFEST, a phase 2 study of CPI-0610, a Bromodomain and Extraterminal Domain inhibitor (BETi), in combination with ruxolitinib, in JAK inhibitor (JAKi) treatment naïve myelofibrosis patients. Presented at: 2019 ASH Annual Meeting, Orlando, FL, December 7-10, 2019. Abstract 4164. bit.ly/2LCVQNi.

CPI-0610 showed promising spleen volume responses and a meaningful reduction in total symptom score as monotherapy and in combination with ruxolitinib (Jakafi) for patients with refractory or intolerant advanced myelofibrosis.

CPI-0610 Shows Strong Efficacy Signals for Advanced Myelofibrosis

The BTK inhibitor zanubrutinib (Brukinsa) continues to demonstrate high overall response rates (ORR) for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL), regardless of the presence of high-risk cytogenetics, according to findings from the SEQUOIA trial and updated results from the AU-003 trial presented at the 2019 ASH Annual Meeting.

 the ORR with zanubrutinib was 92.7% (95% CI, 86%-96.8%) for treatment-naive patients with del(17p) CLL/SLL. After 29.5 months of follow-up in the AU-003 trial,

 the ORR was 100% in treatment-naive patients with CLL/SLL. In the relapsed/refractory setting, zanubrutinib elicited an ORR of 95%.  

"With further follow-up and experience, zanubrutinib monotherapy was found to be well-tolerated and active in patients with CLL/SLL, irrespective of del(17p) status," Constantine S. Tam, MBBS, MD, from the Peter MacCallum Cancer Centre, said while presenting the results from both studies. "The complete response rate [in AU-003] was 16% and continues to mature over time."  

Arm C of the SEQUOIA trial included 109 patients with del(17p) CLL/SLL. The median age of patients was 70 years, and 12.8% had an ECOG performance status of 2. The median number of months since diagnosis was 21.62. In addition to del(17p), 66.1% of patients also harbored del(13q), 33.9% had del(11.q), 18.3% had Trisomy 12, and 61.5% had unmutated IGHV.  

At a median follow-up of 10.0 months, there were 2 complete responses (CR; 1.9%), 86 partial responses (PR; 78.9%), and 13 PRs with lymphocytosis (11.9%). Overall, 95% of patients had a duration of response lasting 6 months or longer, and similar response rates were seen across all patient subgroups.  

Overall, 36.7% of patients experienced a grade ≥3 adverse event (AE), with the most common events being neutropenia (10.1%), pneumonia (3.7%), and hypertension (2.8%). Serious AEs were experienced by 23.9% of patients. There was 1 grade 5 case of pneumonia that led to sepsis and eventually death for the patient. Grade ≥3 infection occurred in approximately 10% of patients and major bleeding was seen in nearly 4% of individuals. Grade ≥3 atrial fibrillation was experienced by 0.9% of patients.  

"In this very large cohort of de novo del(17p) patients treated with frontline zanubrutinib, the overall response rate was high at 92.7%. The drug was well tolerated, and the toxicity profile was consistent with what is already published for zanubrutinib," said Tam. 

AU-003 was the first study to explore zanubrutinib in humans and provides the longest available follow up for the BTK inhibitor. At this point, 384 patients have been enrolled in the trial, including 123 with CLL/SLL. The median age of patients with CLL/SLL was 67 years, with 22 having treatment-naive disease and 101 have relapsed or refractory CLL/SLL. The most common molecular risk factor was unmutated IGHV (68.3%) and 16.2% of patients had del(17p).  

Responses in the treatment-naive group consisted of 5 CRs (22.7%) and 17 PRs (77.3%). In this group, 95.2% of patients continued to respond at the time of the assessment. In the relapsed/refractory cohort, responses consisted of 14 CRs (13.9%), 73 PRs (72.3%), and 8 PRs with lymphocytosis (7.9%). Responses continued for 97.6% of patients. Across both groups combined, the ORR was 95.9% and the CR rate was 15.4%. 

In patients with del(17p) CLL/SLL, the ORR was 100% in the treatment naive group, which were all PRs (n = 3). In the relapsed/refractory del(17p) group, the ORR was 92.3%, with 1 CR (7.7%). All patients continued to respond at the time of the assessment.  

In the treatment-naive group, the 12-month and 24-month progression-free survival (PFS) rates were 95% and 97%, respectively. For the relapsed/refractory group, the 12-month and 24-month PFS rates were 97% and 91%, respectively.  

Across the study, grade ≥3 AEs of any cause were seen in 61.8% of patients receiving zanubrutinib, with AEs leading to discontinuation for 4.1% of patients. Serious AEs were experienced by 47.2% of patients, with one fatal adverse event that was deemed unrelated to study drug. The most common AEs were contusion (47.2%), upper respiratory tract infection (42.3%), diarrhea (31.7%), cough (29.3%), headache (23.6%), and fatigue (20.3%). Grade ≥3 atrial fibrillation occurred in 1.6% of patients.  

"If you break down when these adverse events happen, you see that the most troublesome adverse events, including neutropenia, atrial fibrillation, opportunistic infection, and pneumonia, all tend to occur early with a reduced risk in the third year of treatment," said Tam. "There is a constant approximately 10% risk of grade 3 infection year-by-year, which actually seems high at first glance but is in fact totally consistent with other BTK inhibitors in this same population."  

Other arms of the phase III SEQUOIA trial continue to enroll, including an arm comparing zanubrutinib with bendamustine plus rituximab for treatment-naive CLL/SLL (NCT03336333). Additionally, the phase III ALPINE study is currently recruiting to explore zanubrutinib compared with ibrutinib for patients with relapsed/refractory CLL. The primary completion date for this trial is February 2021 (NCT03734016).  

Tam CS, Robak T, Ghia P, et al. Efficacy and safety of zanubrutinib in patients with treatment-naïve chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) with del(17p): initial results from arm C of the Sequoia (BGB-3111-304) trial. Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 499. bit.ly/2rkuTqP.           

Cull G, Simpson D, Opat S, et al. Treatment with the Bruton tyrosine kinase inhibitor zanubrutinib (BGB-3111) demonstrates high overall response rate and durable responses in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): updated results from a phase 1/2 trial. Presented at: 2019 ASH Annual Meeting; December 7-10, 2019;  Orlando, FL. Abstract bit.ly/355AShI.

The BTK inhibitor zanubrutinib continues to demonstrate high overall response rates for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma, regardless of the presence of high-risk cytogenetics.

Zanubrutinib Effective in CLL/SLL, Regardless of Del(17p) Status

More than half of patients with heavily pretreated B-cell malignancies responded to the noncovalent BTK inhibitor LOXO-305, including those with resistance or intolerance to other BTK inhibitors or BCL2 inhibitors, according to findings from the phase I/II BRUIN trial presented at the 2019 ASH Annual Meeting.

For patients with previously treated chronic lymphocytic leukemia (CLL), the objective response rate (ORR) was 77% with LOXO-305. Of these patients, 75% had received a prior BTK inhibitor. For patients with mantle cell lymphoma (MCL), the ORR was 50%, with 88% of patients having received a prior BTK inhibitor. Additionally, LOXO-305 was well tolerated, with most adverse events (AEs) being grade 1 or 2 in severity. There were no cases of atrial fibrillation or major bleeding and contusions only occurred in 11% of patients.

“LOXO-305 demonstrates significant antitumor activity across patients with CLL as well as MCL. Activity was observed at all dose levels,” Anthony Mato, MD, director of the CLL Program at Memorial Sloan Kettering Cancer Center, said in a press release. “LOXO-305 was quite safe, with a safety and tolerability profile consistent with highly selective drug design, there’s been no evidence of off-target effects. Collectively these data demonstrate that BTK remains a highly actionable target, despite progression on covalent BTK inhibitors.”

Prior approved BTK inhibitors, such as ibrutinib (Imbruvica), covalently bond with the kinase whereas LOXO-305 utilizes noncovalent bonding. This difference allows for higher affinity across BTK, including in resistance mutations such as C481, Mato said. Moreover, this difference could lessen the toxicity profile and make the agent more ideal for combination strategies, he said.

"LOXO-305 is a highly potent and selective noncovalent inhibitor of both wild-type as well as C481-mutant BTK. LOXO-305 was designed with the intent to achieve noncovalent BTK binding, regardless of C481 status with nanomolar potency and high selectivity for BTK," he said. "All of these taken together reveal a molecule with the potential to be well tolerated in key patient populations, like those who are BTK inhibitor naïve, BTK inhibitor relapsed patients—regardless of C481 status&mdash;those who are BTK intolerant, as well as after other novel therapies including BCL2 inhibitors and PI3K inhibitors."

The phase I/II study had enrolled 28 total patients across a variety of LOXO-305 doses that ranged from 25 mg to 200 mg. The most common diagnosis was CLL (n = 16) followed by MCL (n = 8). Additionally, other B-cell malignancies included were Waldenström macroglobulinemia (n = 2), diffuse large B cell lymphoma (n = 1), and marginal zone lymphoma (n = 1).

Patients in the CLL and other groups had received a median of 4 prior therapies. Those in the MCL group, specifically, had received a median of 3 prior therapies. The median age across all patients was 66 years and most had an ECOG performance status of 0 (68%). Seventy-one percent of patients were IGHV unmutated. Across all patients, the primary reasons for discontinuing a prior BTK inhibitor was for progressive disease (64%), intolerance (18%), or for another reason (18%).

In the CLL group, 10 of 13 evaluable patients responded to LOXO-305, which consisted of 8 partial responses (PRs) and 2 PRs with lymphocytosis. Responses were seen in patients both with and without the C481S acquired mutation, which causes resistance to prior BTK inhibitors. Additionally, responses to LOXO-305 were seen in patients with the BCL G101V mutations, a resistance mechanism to BCL2 inhibitors.

In the MCL group, there were 6 evaluable patients at the time of the analysis. Of these, 1 had a complete response and 2 had PRs. Of these responders, 2 had receive prior BTK therapy; however, none had the acquired C481 resistance mutation. Fifty percent of those with other B cell malignancies besides CLL or MCL had a minimal response and the other 50% had stable disease.

At the time of the assessment, 86% of patients remained on therapy, including all patients in the CLL group. Ninety-four percent of patients in the trial had at least some reduction in lymphadenopathy, Mato said, and 64% of patients met the threshold of greater than 50% reduction in lymphadenopathy.

The majority of AEs were grade 1/2 in severity with just 2 grade ≥3 treatment-related AEs reported with LOXO-305 (leukocytosis and transient neutropenia). The most frequently observed treatment-emergent grade 1/2 AEs were fatigue (25%), diarrhea (18%), anemia (14%), rash (14%), arthralgia (11%), back pain (11%), hyperbilirubinemia (11%), and contusion (11%).

"Having treated several of these patients, I can tell you that these adverse events were quite manageable. No grade 3/4 events were notable. In addition, there were no observations of notable covalent BTK AEs, such as atrial fibrillation or major bleeding, despite very frequent monitoring. We conducted over 780 EKGs on this trial," said Mato. "There were no dose-limiting toxicities and the maximum tolerated dose was not reached."

The phase I/II study continues to enroll participants, with a goal of recruiting 190 patients. The estimated primary competition day for the study is October 2020 (NCT03740529). There are plans to expand this trial with the addition of rational combinations, Mato noted.

Mato AR, 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. Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 501. bit.ly/354T4b5.

More than half of patients with heavily pretreated B-cell malignancies responded to the noncovalent BTK inhibitor LOXO-305, including those with resistance or intolerance to other BTK inhibitors or BCL2 inhibitors.

LOXO-305 Is Highly Effective in Heavily Pretreated B-cell Malignancies

The triplet of umbralisib, ublituximab, and venetoclax (Venclexta) induced a complete remission (CR) rate of 44% as a treatment for patients with relapsed/refractory chronic lymphocytic leukemia (CLL), according to findings from a phase I/II dose escalation study presented at the 2019 ASH Annual Meeting.

At the end of 12 cycles of treatment with the regimen, the objective response rate (ORR) was 100%, which included the CR rate of 44%. In an assessment of peripheral blood, all patients were negative for minimal residual disease (MRD). In the bone marrow, 78% were MRD-negative (<.01%) and 22% were MRD intermediate (.01% to 1.0%). At a median follow-up of 6.4 months (range, 0.7-19.0+), no patients had progressed.

"There's early evidence of MRD-negativity, and all patients will continue follow up for MRD in the peripheral blood every 6 months," Paul M. Barr, MD, Wilmot Cancer Institute, University of Rochester, said during the presentation. "The study has a been expanded to explore the combination in Richter's transformation as well as mantle cell lymphoma. A large phase II study has been initiated, termed the ULTRA-V study, to further explore the regimen with the intention of gaining regulatory approval."

Umbralisib is a dual PI3K delta and CK1 epsilon inhibitor that has a unique structure and improved tolerability compared with other agents in the class, Barr said. Ublituximab is a glycoengineered CD20 inhibitor and venetoclax is a BCL2 inhibitor. The combination is backed by preclinical evidence showing synergistic cytotoxicity between inhibition of the B cell receptor and BCL2. Additionally, targeting PI3K could help prevent resistance to BCL2 inhibition.

At the time of the analysis, 27 patients were evaluable for safety and 23 were assessable for efficacy. The median age of patients was 63 years, and 81.4% had ECOG performance status of 1. The median creatinine clearance at baseline was 75 mL/min and the median number of prior regimens was 1 (range, 1-5). A quarter of patients were refractory to their immediate prior therapy (26%). Prior exposure to a BCL2 or PI3K inhibitors was allowed before study entry. Prior BTK inhibition was also permitted, with a 21-day washout period. Overall, 54% of patients were refractory to a BTK inhibitor. More than half of patients (52%) had at least 1 high-risk feature.

Ublituximab and umbralisib were administered together as induction in the first 3 cycles before the addition of venetoclax, to abate the risk of tumor lysis syndrome (TLS). Ublituximab was only administered during the 3-cycle induction period. Consolidation with venetoclax and umbralisib lasted from cycle 4 to cycle 12. Those testing positive for MRD after consolidation could continue to receive umbralisib monotherapy.

Ublituximab was infused at a fixed 900 mg dose on days 1/2, 8, and 15 of cycle 1 and then day 1 of the next 2 cycles. Daily umbralisib was escalated from 600 mg to 800 mg, with 3 patients receiving the 600 mg dose and 6 the 800 mg dose, which was recommended for phase II studies. An additional 18 patients were enrolled at the 800 mg dose in the phase II portion of the study. Venetoclax was administered at the standard 5-week ramp up dosing to 400 mg in the consolidation period.

Following induction therapy, there was a mean 61% reduction from baseline in lymph node size with an ORR of 87%. By cycle 7, the ORR was 100%. At the end of the consolidation period (cycle 12), mean lymph node size had declined by 87%. Absolute lymphocyte count, which was a mean of 48,000 per μL at baseline, declined to 3400 per μL by the end of cycle 6.

"Although it's a relatively small cohort with short follow up, there doesn't seem to be any differences in treatment effect duration for those treated with prior BTK inhibitors," said Barr. "No patients have progressed with CLL, although it is a relatively short follow up of only 6 months."

During the induction phase, 1 patient discontinued the study to address grade 3 rash. Additionally, in the consolidation portion, 1 patient discontinued due to grade 3 diarrhea. There was 1 dose-limiting toxicity seen at the 800 mg dose of umbralisib, namely a lower gastrointestinal (GI) bleed that resolved in 3 days. The maximum tolerated dose was not reached, and dose modifications were relatively infrequent.

There were no cases of clinical or laboratory TLS and no patients developed grade 3/4 liver function test elevations. The most common all-cause grade 3/4 adverse events (AEs) were neutropenia (19%), leukopenia (15%), infusion reaction (7%), deep vein thrombosis (7%), anemia (4%), diarrhea (4%), rash (4%), lower GI bleed (4%), supra ventricular tachycardia (4%), anxiety (4%), hypophosphatemia (4%), and dyspnea (4%).

"Umbralisib, ublituximab, and venetoclax appears to be well tolerated at the phase II dose," said Barr. "The 3-cycle induction effectively mitigates TLS risk. Myelosuppression and GI effects were very manageable, with low risk of discontinuation so far."

Findings from the study will continue to mature, with a 12-month analysis planned. Additionally, the phase II portion of the study continues to enroll participants, with a recruitment goal of 30 (NCT03379051). The ULTRA-V study plans to enroll 90 patients with treatment-naive and relapsed/refractory CLL (NCT03801525).

Venetoclax (U2-Ven) in Patients with Relapsed/Refractory CLL. Presented at: 2019 ASH Annual Meeting, Orlando, FL, December 7-10, 2019. Abstract 360.

The triplet of umbralisib, ublituximab, and venetoclax induced a complete remission rate of 44% as a treatment for patients with relapsed/refractory chronic lymphocytic leukemia.

Silas Inman