Lisa Astor

The novel immunotherapy AMG 509 has demonstrated promising preclinical activity in STEAP1-expressing prostate cancer cells. Results of the ongoing first-in-human study of AMG 509 in patients with metastatic castration-resistant prostate cancer (mCRPC) are anticipated.

In a presentation during the 27th Annual Prostate Cancer Foundation Scientific Retreat, W. Kevin Kelly, DO, explained the potential of this novel agent and its development progress.

“In the preclinical studies, AMG 509 shows potent tumor progression in vitro and in vivo. We are currently building AMG 509 in a phase 1 first-in-human study in patients with relapsed or refractory metastatic CRPC. This study is now open and recruiting patients,” said Kelly, director of the Division of Solid Tumor Oncology in the Department of Medical Oncology, Sidney Kimmel Medical College at Thomas Jefferson University, and associate director of translational research at the Sidney Kimmel Cancer Center in Philadelphia, Pennsylvania.

AMG 509 is a bispecific monoclonal antibody (mAb), specifically a bispecific XmAb 2 + 1, directed against six transmembrane epithelial antigen of the prostate 1 (STEAP1)–expressing cells. The agent consists of an anti-CD3 single chain variable fragment that binds T cells, 2 humanized anti-STEAP1 Fab domains, and an effectorless Fc domain to extend the half-life, and was designed to redirect T-effector cells to kill STEAP1-expressing cells.

STEAP1 is detected at elevated levels in about 88% of mCRPC samples by immunohistochemistry (IHC) and also at low levels in normal prostate cells, making it an exciting target in prostate cancer. “STEAP1 is truly a prostate-specific target,” Kelly commented.

AMG 509 works by simultaneously binding to CD3-positive T cells and STEAP1-positive cancer cells, at which point the agent triggers CD3 clustering at the surface of T cells as well as T-cell–mediated redirected lysis of the STEAP1-positive cancer cells.

“By binding to the surface STEAP1 on tumor cells and surface CD3 on T cells, AMT 509 redirects a patient’s T cells to attack and eradicate cancer cells,” Kelly explained. “The payload here is the patient’s own T cells. Importantly, AMG 509 triggers activation and proliferation of the patient’s own T cells, which are certainly capable of killing cancer cells.”

In vitro, AMG 509 demonstrated potent and selective T-cell–mediated destruction of STEAP-1-expressing cancer cells in both prostate cancer and Ewing sarcoma cancer cell lines.

Kelly noted that AMG 509 had greater activity in cell lines with higher levels of STEAP1. Approximately 84% of primary prostate tumors express levels of STEAP1 that would be sufficient for AMG 509 activity, which was considered to be above 62 fragments/kilobase/million on RNA sequencing. Metastatic lesions were found to express higher STEAP1 levels even than primary tumors.

In a 22RV1 cell prostate xenograft model, treatment with AMG 509 led to increased T-cell infiltration. Responses were seen even at doses as low as 0.1 mg/kg.

An open-label phase 1 study was initiated in January 2020 to assess the potential of AMG 509 in patients with mCRPC (NCT04221542); the trial is currently enrolling patients.

The study consists of a dose-exploration and a dose-expansion phase with 40 patients expected to be enrolled in the first phase and 30 in the second. In the dose-exploration phase, the investigators are looking to determine the maximum tolerated dose and recommended phase 2 dose for AMG 509. In the expansion phase, the primary outcomes are the safety and tolerability of the agent. Second outcome measures include pharmacokinetic parameters, objective response rate, prostate-specific antigen response, overall survival, and circulating tumor cell response.

Patient eligibility criteria consist of confirmed mCRPC that is refractory to novel hormonal therapies and disease that has failed 1 to 2 prior taxane regimens or the patient is not suited for taxane therapy. Additionally, patients are required to have adequate hematologic, renal, hepatic, and cardiac function. Those with disease requiring immunosuppressive therapy, untreated central nervous system or leptomeningeal disease, or small cell or neuroendocrine carcinoma of the prostate are excluded from the trial.

Kelly WK, Danila DC, Edenfield WJ, et al. Phase 1 study of AMG 509, a STEAP1 x CD3 T cell–recruiting XmAb 2+1 immune therapy, in patients with metastatic castration resistant prostate cancer (mCRPC). Presented at: 27th Annual Prostate Cancer Foundation

Articles

In a presentation during the 27th Annual Prostate Cancer Foundation Scientific Retreat, W. Kevin Kelly, DO, explained the potential of this novel agent and its development progress.







Novel Bispecific Monoclonal Antibody Demonstrates Preclinical Promise Against STEAP1 Target in mCRPC 

A novel tubulin inhibitor VERU-111 has demonstrated promising early antitumor activity and tolerability in men with metastatic castration-resistant prostate cancer (mCRPC) who have failed prior androgen receptor (AR) therapy, according to the results of a phase 1b/2 study (NCT03752099).

“VERU-111 appears to be well tolerated in our phase 1 study. Seventy-three mg daily was the maximum tolerated dose; however, given toxicities, we elected to move forward with 63 mg per day continuous dosing. Daily chronic drug administration is safe and feasible, and we have shown preliminary evidence of antitumor activity including PSA [prostate-specific antigen] reductions, objective responses, and some durable responses,” summarized Mark C. Markowski, MD, PhD, when presenting the findings in a poster presentation during the 27th Annual Prostate Cancer Foundation Scientific Retreat.

Based on the positive results of the phase 1b portion and meetings with the FDA in July 2020, the developer, Veru Inc, plans to initiate a pivotal phase 3 trial by the first quarter of 2021. The FDA has already provided input on the design of the phase 3 trial and designated that the primary end point would be radiographic progression-free survival. Final protocols for the phase 3 trial will be submitted to the FDA by the end of the fourth quarter of 2020.

The phase 2 portion of the current study has already enrolled a full 40 patients with mCRPC who have failed at least 1 prior AR-targeting therapy and intravenous chemotherapy and is assessing the use of VERU-111 in these patients at the recommended phase 2 dose. The primary end point is radiographic progression-free survival.

VERU-111 is an oral, first-in-class, selective small molecule that binds to the colchicine binding site to crosslink both the α and β tubulin subunits of microtubules. In preclinical studies, VERU-111 demonstrated the ability to decrease production of β tubulin isoforms, cleave the PARP protein, and induce apoptosis in both taxane-resistant and enzalutamide (Xtandi)–resistant CRPC cell lines.

The dose-escalation phase 1b portion of the clinical trial enrolled 39 men with mCRPC following at least 1 prior AR-targeted therapy across 7 sites in the United States. Patients were allowed to have received up to 1 prior lines of taxane-based chemotherapy for metastatic disease.

The study explored 2 potential dosing schedules: a 7-day dosing schedule with VERU-111 administered orally at each dose level for 7 days on and 14 days off in 21-day cycles, and an expanded dose schedule of 14 days on and 7 days off if the 7-day dosing schedule was tolerated. If the expanded dosing was tolerated, then VERU-111 would be given continuously. Doses of VERU-111 from 4.5 mg to 81 mg were explored.

Of the 39 patients, the median age was 74 years (range, 61-92) and patients had a median Gleason score of 8 (range, 5-10). The majority of patients had an ECOG performance status of 0 (54%) and metastatic disease to the bone (55%). Prior therapy included abiraterone acetate (Zytiga) in 79%, enzalutamide in 64%, abiraterone and enzalutamide in 44%, and taxane-based chemotherapy in 23%.

Ten patients were graduated to continuous dosing of VERU-111 and have received at least 4 cycles of continuous dosing. In these patients, the best objective tumor responses seen included 2 partial responses and 8 patients with stable disease. The median duration of treatment without radiographic progression was more than 11 months (range, 6.0-18). Sixty percent had a decrease in PSA levels, with 20% having a decrease of ≥50%. Three of the patients are still on treatment. An additional 2 objective responses were observed in patients who have not yet reached 4 cycles.

Across all dose levels, the most frequent treatment-related adverse events (AEs) were diarrhea, fatigue, and nausea. Grade ≥3 treatment-related AEs included diarrhea in 3 patients, fatigue in 3, nausea in 3, anemia in 1, and vomiting in 1 patient. Incidence of treatment-related AEs increased at dose levels of 63 mg and above. As such, the recommended phase 2 dose of VERU-111 was determined to be 63 mg.

“The maximum tolerated dose was 72 mg per day daily dosing; however, given the 3 instances of grade 3 or higher diarrhea, we elected to move forward with the 63 mg daily dose cohort. Of note, we saw few instances of neutropenia and we did not observe significant neuropathy,” said Markowski, assistant professor of oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland.

A total of 25 patients were treated at the 63 mg daily dose for at least 1 cycle of treatment. Among these patients, observed drug-related AEs included diarrhea in 56%, nausea in 24%, decreased appetite in 12%, fatigue in 12%, dysgeusia in 12%, weight loss in 12%, vomiting in 8%, and low white blood cell count in 8%. Most AEs were either grade 1 or 2. Only one patient experienced a drug-related grade 3 AE of fatigue at the 63-mg dose. The fatigue resolved when the dose was reduced to 54 mg.

Among 16 evaluable patients treated with 63 mg or higher of VERU-111, the median duration of treatment was 5.8+ months and the mean duration was 6.8+ months (range, 0-15.4). Five patients discontinued treatment due to AEs. Of the other 11 patients, the median duration of treatment was 9.8+ months and the mean duration was 9.0+ months (range, 2-15.4+).

Seven patients remained on the study as of data cutoff. Their median duration of exposure was 10.5+ months and the mean duration was 10.2+ months (range, 4.2-15.4+).

1. Markowski MC, Eisenberger MA, Tutrone R, et al. Phase 1b/2 study of VERU-111, novel, oral tubulin inhibitor, in men with metastatic castration resistant prostate cancer (mCRPC) who failed an androgen receptor targeting agent. Presented at: 27th Annual Prostate Cancer Foundation Scientific Retreat; October 20-23, 2020; Virtual.

2. Veru receives positive input from FDA on phase 3 pivotal trial to evaluate VERU-111 in metastatic castration resistant prostate cancer. News release. Veru Inc. July 23, 2020. Accessed October 22, 2020. https://bit.ly/3kliZTz

A novel tubulin inhibitor VERU-111 has demonstrated promising early antitumor activity and tolerability in men with metastatic castration-resistant prostate cancer who have failed prior androgen receptor therapy, according to the results of a phase 1b/2 study.

VERU-111 Shows Early Promise and Safety in mCRPC After Progression on AR Therapy

to help summarize the best treatment for patients with mantle cell lymphoma (MCL) across various stages based on the greatest level of evidence available and the most up-to-date data. However, ahead of the eighth annual Society of Hematologic Oncology (SOHO) Meeting, Robert Marcus, MA, FRCP, FRCPath, chair of the MCL session, said, “The landscape has completely changed as a consequence of COVID[-19].”

“Based on the climate, I think we are beginning to change our practice,” said Marcus, a consultant hematologist for HCA Healthcare UK, in an interview. “And I think that the takeaway message now is you need to consider the environment in which you practice….that environment now includes the risk of Covid 19 [coronavirus disease 2019] infection.”

A great deal of discussion revolves around standard-of-care induction regimens for patients with MCL and which option to choose. Although many hematologic oncologists have their preferred regimens, the National Comprehensive Cancer Network (NCCN) guidelines for MCL recommend a number of preferred chemotherapy-based treatment regimens, whether a patient is eligible for stem cell transplantation or not, usually followed by maintenance rituximab (Rituxan).

Marcus noted that in the United Kingdom, for example, oncologists typically use the Nordic regimen of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) and high-dose cytarabine, followed by stem cell transplant for those who are eligible and maintenance therapy.

Steven Le Gouill, MD, PhD, of Nantes University Hospital in France, discussed available options for frontline treatment of patients with MCL and data supporting the various options. Optimal use of these chemoimmunotherapy regimens are constantly being refined for specific patient populations and compared to determine which combination leads to better outcomes.

Marcus suggested that in MCL treatment, as with other hematologic malignancies, there is increasingly a push to move away from chemotherapy-based regimens. As such, studies are examining the possibility of moving regimens such as combinations with Bruton tyrosine kinase (BTK) inhibitors into earlier settings.

Michael Wang, MD, of The University of Texas MD Anderson Cancer Center, presented subgroup findings from the SYMPATICO trial of 1 such chemotherapy-free frontline regimen of ibrutinib (Imbruvica) and venetoclax (Venclexta) for the treatment of older patients with MCL or those with a 

Previous data released from the safety run-in portion of this phase 3 trial demonstrated a manageable safety profile for the combination with no clinical cases of tumor lysis syndrome reported and few dose-limiting toxicities observed.

The use of BTK inhibitors in the relapsed setting, however, is well established and has played a significant role in the treatment of patients with MCL over the past several years, starting with the first-generation BTK inhibitor ibrutinib, which now has more than 7 years of follow-up data.

In a recent analysis of pooled data for the use of ibrutinib in patients with relapsed/refractory MCL with extended follow-up of up to 7.5 years, the BTK inhibitor induced a median progression-free survival of 25.4 months (95% CI, 17.5-51.8) and a median overall survival of 61.6 months (95% CI, 36.0-not evaluable) among patients who had only received 1 prior line of therapy.

First-generation ibrutinib has been associated with an increased risk of atrial fibrillation and bleeding, but these adverse effects are generally manageable. Use of newer second-generation BTK inhibitors, such as acalabrutinib (Calquence) and zanubrutinib (Brukinsa), are associated with reduced rates of atrial fibrillation and are gaining popularity as physicians become more comfortable with them. However, results of head-to-head comparisons between these BTK inhibitors have yet to be published

For patients who relapse, do not respond, or are intolerant to BTK inhibitors, treatment options become more limited. The latest addition to the treatment paradigm for MCL in the relapsed/refractory setting is the CAR T-cell agent brexucabtagene autoleucel (formerly KTE-X19; Tecartus), which was approved by the FDA on July 24, 2020.

This represents the first chimeric antigen receptor (CAR) T-cell therapy approved for the treatment of MCL. The approval was based on findings from the phase 2 ZUMA-2 trial, which demonstrated an objective response rate of 93% among the first 60 patients treated with the CAR T-cell agent and a complete response rate of 67%. The overall response rate was 85%, with complete responses in 59%. At 1 year, the estimated overall survival rate was 83%.

However, because brexucabtagene autoleucel was associated with significant toxicities, including risk of cytokine release syndrome and neurologic toxicities, the FDA required the implementation of a risk evaluation and mitigation strategy (REMS) 

Brexucabtagene autoleucel was quickly added to the most recent edition of the NCCN guidelines (updated August 4) as a new treatment option after the use of chemoimmunotherapy and BTK inhibition.1 The guidelines also call attention to the potentially severe toxicities from treatment and stress that any facility that administers brexucabtagene autoleucel must be enrolled in the REMS program.

The use of CAR T-cell therapy is interesting, Marcus said, but suggested that it may only be used when there are no other less toxic options for the patient.

The various treatment options available in the relapsed setting were reviewed during the meeting in a presentation by Jonathon B. Cohen, MD, MS, of the Winship Cancer Institute of Emory University School of Medicine in Atlanta, Georgia.

Treatment recommendations for patients with MCL may be changed significantly, however, due to the coronavirus disease 2019 (COVID-19) pandemic. 

To avoid the risk of infection, oncologists are considering the use of treatments that would allow patients to avoid coming into medical facilities. Typically, nonchemotherapeutic agents, such as BTK inhibitors, are saved for later lines of therapy in MCL, but Marcus said that hematologic oncologists are questioning whether these agents should now be considered for earlier lines of therapy—despite the findings of randomized trials—to avoid frequent attendance for infusional chemotherapy in medical centers because these patients are often immunosuppressed, putting them at even higher risk for contracting the virus.

“The environment of this pandemic means that we should be actively considering chemotherapy-free combinations, even if the data aren’t quite strong enough yet , because although the alternative in terms of freedom from disease might be better, the risk of dying and the long term consequences of infection are significantly 

greater,” Marcus said. “I think there will have to be some adaptations of our therapy, according to the immunosuppression associated with new and old therapy, and of course, not just the immunosuppression, but the facility and the country where such patients are treated .”

As such, rather than the standard induction regimens like hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) and R-CHOP, many physicians and their patients may turn to chemotherapy-free options like ibrutinib so that patients can continue treatment indefinitely from home with telehealth follow-ups every few months.

Additionally, Marcus suggested that the threshold for patients with low-grade MCL who require therapy will be raised. Many patients with MCL do not require treatment, especially those with indolent, asymptomatic disease, and are instead observed until the disease becomes 

symptomatic and/or more aggressive. However, this management plan may now have to extend beyond this specific patient population to more patients with low-grade disease, and active treatment will be prioritized only for patients who cannot delay treatment.

The European Society for Medical Oncology has released a set of guidelines for the management of patients with cancer during the COVID-19 pandemic. The guidelines offer recommendations for the prioritization of treatment for patients with MCL.

These guidelines suggest that induction therapy is high priority, although treatment schedules can be altered to reduce the number of clinic visits, and that granulocyte colony-stimulating factor support can be given to avoid neutropenia. Systemic therapy in the setting of relapsed disease can also be modified to reduce the number of visits, but T-cell suppressive agents should be avoided. Other treatments may be delayed, including consolidation and maintenance therapy. 


“We are considering whether or not bendamustine is the right drug to give for patients considering the associated long term T-cell suppression, and we are considering how many visits patients need to make to the hospital for chemotherapy given the current risk of COVID-19,” Marcus said. “I think that there’s going to be a reduction in intensity of therapy [for] patients with all hematologic malignancies except for the truly curable.

“I think there’s a whole series of factors which will, apart from the efficacy of the drugs themselves, have a major influence on the way we practice in the COVID[-19] era.”

1. NCCN Clinical Practice Guidelines in Oncology. B-cell lymphomas, version 3.2020. Accessed August 10, 2020. https://bit.ly/3ipqKGS

2. Wang M, Ramchandren R, Chen R, et al. Results from the safety run‐in period of the SYMPATICO study evaluating ibrutinib in combination with venetoclax in patients with relapsed/refractory mantle cell lymphoma. 

2019;37(S2):333-335. doi:10.1002/hon.146_2630

3. Rule S, Dreyling MH, Goy A, et al. Long-term outcomes with ibrutinib versus the prior regimen: a pooled analysis in relapsed/refractory (R/R) mantle cell lymphoma (MCL) with up to 7.5 years of extended follow-up. 

2019;134(suppl 1):1538. doi:10.1182/blood-2019-124691

4. FDA approves brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma. News release. FDA. July 27, 2020. Accessed August 10, 2020. https://bit.ly/3gVeKwo

5. Wang M, Munoz J, Goy A, et al. KTE-X19 car T-cell therapy in relapsed or refractory mantle-cell lymphoma. 

2020;382(14):1331- 1342. doi:10.1056/NEJMoa1914347

6. ESMO management and treatment adapted recommendations in the COVID-19 era: diffuse large B-cell lymphoma, mantle cell lymphoma and aggressive T-cell lymphomas. European Society of Medical Oncology. Accessed August 10, 2020. https://bit.ly/3fIw86c

“The landscape has completely changed as a consequence of COVID[-19]," says  Robert Marcus, MA, FRCP, FRCPath.

Guidelines for MCL Set to Change Due to COVID-19

Traditional frontline chemoimmunotherapy 

regimens used to be the gold standard for treating patients with newly diagnosed chronic lymphocytic leukemia (CLL). However, over time, targeted therapies have been inching out the use of chemoimmunotherapy to become the preferred approach in this setting.

“I think as time goes on, and more and more data emerge, we are getting further and further from chemotherapy,” said Susan M. O’Brien, MD, associate director for Clinical Science at the Chao Family Comprehensive Cancer Center, and medical director of the Sue and Ralph Stern Center for Clinical Trials and Research, University of California, Irvine.

Oncology (SOHO) Annual Meeting, O’Brien, the 2021 president-elect of SOHO, spoke with the SOHO Daily News about the reason for this change in the treatment paradigm for CLL, why there is still a place for chemoimmunotherapy in the armamentarium, and some of the related data that will be discussed during the meeting.

Defining the Place for Chemoimmunotherapy

Cytotoxic chemotherapy-based regimens are often difficult for patients to tolerate, especially among older patients who may be unfit or have several comorbidities. Treatments with newer targeted approaches, such as Bruton tyrosine kinase (BTK) inhibitors and BCL-2 inhibitors, are often associated with significant efficacy and manageable toxicity profiles.

O’Brien noted that the use of the common intensive chemoimmunotherapy regimen FCR (fludarabine, cyclophosphamide, and rituximab [Rituxan]), due to the degree of myelosuppression and risk of infection, is usually reserved for patients who are younger and fit. Those who are older, have significant comorbidities, or are unfit are expected to not be able to tolerate the regimen. Guidelines, such as those from the National Comprehensive Cancer Network, echo this sentiment and do not recommend the use of the FCR regimen except in patients who are under 65 years old and without significant comorbidities.

FCR is one of the chemoimmunotherapy regimens that has shown positive long-term data in the treatment of CLL. In the CLL8 trial, the addition of rituximab to the chemotherapy regimen induced a median progression-free survival (PFS) of 56.8 months.

 The median overall survival (OS) was not reached after a median follow-up of 5.9 years compared with a median OS of 86.0 months in the chemotherapy arm (HR, 0.68; 95% CI, 0.54-0.89; 

Many oncologists are more comfortable with such chemoimmunotherapy regimens due to their experience with the regimens and the availability of long-term data for these treatments; so, they can know what to expect long term. Many of the newer targeted therapies do not have significant long-term data available, with the exception of the first-generation BTK inhibitor ibrutinib (Imbruvica).

Additionally, for particular patient populations, the use of FCR is actually preferred over other regimens, even those with newer agents. Among patients with immunoglobulin heavy chain (

mutated CLL, the use of FCR has led to long-term PFS benefit.

In a long-term analysis of a phase 2 study of FCR in patients with CLL, patients with 

mutated disease demonstrated considerable survival benefit over those with unmutated disease. At the median follow-up mark of 12.8 years, the PFS rate was 53.9% for patients with 

mutated CLL (n = 88) compared with 8.7% for those with 

mutated group, 83.0% achieved a complete response and 50.7% achieved minimal residual disease (MRD) negativity compared with 72.2% and 33.0%, respectively, in the population that did not have the mutation.

Further, a plateau was seen in the PFS curve for patients with 

mutated CLL, where no relapses were seen after 10.4 years. Forty-two patients were followed after this point for a median of 2.5 years, but none experienced further relapse.

“That raises the obvious question, is there a cure fraction there? I’m willing to go out on a limb and say that I do think those patients are cured,” O’Brien said. “This is a relatively minor subset because it’s young, fit, and has mutated immunoglobulin. So that’s a very small subset where there still might be a cure fraction. So you could argue that that’s a population [for which] you might still strongly consider chemotherapy.”

Among a majority of patients, however, ibrutinib has demonstrated improved survival outcomes compared with FCR. In the randomized phase 3 E1912 study, in patients with previously untreated CLL who are 70 years of age or Ibrutinib has become a preferred standard of care in the treatment of CLL. The agent was approved for the frontline treatment of patients with CLL based off of findings from the RESONATE-2 trial, in which ibrutinib demonstrated superiority over chlorambucil in patients who were at least 65 years old.

“Ibrutinib has produced longer progression-free survival than any chemotherapy regimen that we have—FCR, BR [bendamustine and rituximab], or chlorambucil,” O’Brien said.

Now with 5 years of follow-up for the study, the median PFS was still not yet reached in the ibrutinib arm compared with 15.0 months (95% CI, 10.2-19.4) with chlorambucil (HR, 0.146; 95% CI, 0.098-0.218). The PFS rate at 5 years was 70% with ibrutinib compared with 12% with chlorambucil. The median OS also was not reached in the ibrutinib arm. At 5 years, the estimated OS rate was 83% with ibrutinib and 68% with chlorambucil.

“These are clearly really durable remissions. So the one thing that I believe [that it] has going for it is the track record. So the longevity is there,” O’Brien said.

Ibrutinib also is considered to be a well-tolerated treatment overall. However, it is associated with an increased risk of atrial fibrillation and bleeding. In the RESONATE-2 trial, the rate of any-grade atrial fibrillation was 16%, and 5% experienced a grade 3 event. The rate of major hemorrhage of any grade was 11% with ibrutinib, and grade 3 or greater major hemorrhage events were observed in 7%.

O’Brien noted that the risk of atrial fibrillation is increased in older men and in those with a history of heart disease. “But would that keep me from using ibrutinib in a 75-year-old patient who was a good candidate for a BTK inhibitor? No, it certainly would not. Because the reality is that most patients can tolerate ibrutinib very well,” she said.

Newer BTK inhibitors, such as acalabrutinib (Calquence), approved in the US, and zanubrutinib (Brukinsa), which is not yet approved for use in CLL but approved for mantle cell lymphoma, are associated with reduced rates of cardiovascular toxicity.

Acalabrutinib in combination with the anti-CD20 monoclonal antibody obinutuzumab (Gazyva) showed significant benefit over the use of chlorambucil plus obinutuzumab in the frontline setting in the phase 3 ELEVATE-TN trial. The median PFS was not reached in the acalabrutinib/obinutuzumab arm compared with 22.6 months with chlorambucil/obinutuzumab (HR, 0.10; 95% CI, 0.06-0.17; 

< .0001). At 2 years, the PFS rate was 93% (95% C I, 87%-96%) with the acalabrutinib combination and 47% (95% CI, 39%-55%) with the chlorambucil combination. Median OS, however, did not vary significantly between the treatment arms.

The median duration of exposure to treatment was 27.7 months with acalabrutinib/obinutuzumab compared with 5.6 months with chlorambucil/obinutuzumab. Even with the longer exposure, the rate of discontinuation due to adverse events was similar between these treatment arms at 11% with acalabrutinib/obinutuzumab and 14% with chlorambucil/obinutuzumab.

In the acalabrutinib combination arm, the most common grade 3 or greater adverse event was neutropenia in 29.8% of patients, followed by thrombocytopenia in 8.4%. Atrial fibrillation of any grade was observed in 3% of patients receiving the acalabrutinib combination and 4% of patients receiving acalabrutinib monotherapy. Grade 3 or greater bleeding events were reported in 2% of patients who received acalabrutinib and obinutuzumab.

One significant benefit of a chemoimmunotherapy approach is the time-limited aspect of the administration of treatment. Whereas treatments such as ibrutinib are administered indefinitely, chemoimmunotherapy is usually given for only 6 cycles, or 6 months. The idea of taking one treatment for years without stopping may be difficult for some patients, especially for younger patients, O’Brien suggested.

“In my experience, it’s rare to find an older patient [who is] not on medication….So, those patients are often used to taking daily medications, and so taking a medication indefinitely, I think, is less of an issue because they’re more used to it. Although it could be a bigger issue in terms of copays if they’re living on fixed income and they have Medicare as their primary [insurance]. But in terms of the psychological impact, it’s less on an older patient and probably more in a younger, fit patient who is somewhat taken aback at the thought that they’re going to take this pill indefinitely,” she explained.

However, a newer agent in the CLL space, the BCL-2 inhibitor venetoclax (Venclexta), is also administered as a fixed-duration treatment. In the frontline setting, venetoclax is given for 12 cycles, and in the relapsed or refractory setting venetoclax is given for up to 24 cycles, or 2 years.

In the frontline setting, venetoclax was assessed in the phase 3 CLL14 trial in combination with obinutuzumab compared with chlorambucil and obinutuzumab in patients with CLL who also had comorbidities. The median PFS was not met in the venetoclax combination arm but showed significant benefit over the chlorambucil combination arm, leading to the regimen’s approval in the frontline setting.

After more than 3 years of follow-up (median, 39.6 months), the median PFS still has not yet been met in the venetoclax arm compared with 35.6 months in the chlorambucil arm (HR, 0.31; 95% CI, 0.22-0.44; 

< .001). The estimated 3-year PFS rates were 81.9% and 49.5% with venetoclax/obinutuzumab and chlorambucil/obinutuzumab, respectively. OS, however, was not significantly different between the 2 arms, and the median was not reached in either arm.9

Additionally, almost half of the patients (47.2%) in the venetoclax arm had undetectable MRD in the bone marrow compared with 7.4% in the chlorambucil arm.

The use of prophylactic treatment and ramping up the dose of venetoclax helped to prevent many cases of tumor lysis syndrome in the venetoclax arm; only 3 cases were reported in the venetoclax arm versus 5 in the chlorambucil arm.

Five patient deaths due to fatal adverse events were reported during treatment in 

the investigational arm compared with 4 in the control arm. After treatment, 11 deaths occurred in the investigational arm versus 4 in the control arm. Most of the fatal events in the venetoclax arm were infections or infestations (1.9% during, 1.9% after), benign or malignant neoplasms (0.5% during, 0.9% after), and cardiac disorders (1.4% after). Secondary cancers were observed in 13.7% of patients treated with the venetoclax combination regimen compared to 10.3% of patients who received the chlorambucil regimen.

Currently, there are no head-to-head comparisons between these small molecules in the upfront setting, making deciding between these available options difficult.

“It’s hard to say that one small molecule is better than another. On the other hand, it’s easy to say that all the great options are clearly producing very durable responses,” O’Brien said. “So how do we decide [between the frontline options] right now? I think we look at the fact that all of them have great efficacy.”

Moving Forward With Combinations and Newer Agents

Rather than choose between BTK or BCL-2 inhibition up front, one possible treatment option could be the use of both in the frontline setting. The use of ibrutinib in combination with venetoclax as treatment for patients with previously untreated CLL has been explored in the phase 2 CAPTIVATE trial; however, the regimen does not have FDA approval. The trial included older patients and those with high-risk disease, including chromosome 17p deletion, mutated 

, chromosome 11q deletion, and/or unmutated 

Treatment was given for a fixed duration of 24 cycles.

PFS and OS rates at 1 year were 98% (95% CI, 94%-100%) and 99% (95% CI, 96%-100%), respectively, with the combination. Seventy-four percent of patients achieved complete remission or complete remission with incomplete count recovery.

In an MRD cohort of the CAPTIVATE trial where patients received 12 cycles of the combination prior to MRD-guided randomized treatment discontinuation, 75% of patients had undetectable MRD in the peripheral blood and 72% in the bone marrow.

“That looks really promising with the very high rates of MRD undetectability,” O’Brien said.

Similarly, an investigator-initiated phase 2 study that combined ibrutinib and venetoclax involving previously untreated high-risk and older patients with CLL demonstrated that after 12 cycles of combined treatment, 88% of the patients had complete remission or complete remission with incomplete count recovery, and 

61% had remission with undetectable minimal residual disease (NCT02756897).12 With combined treatment, the proportions of patients who had complete remission (with or without normal blood count recovery) and remission with undetectable minimal residual disease increased over time.

Moving forward, O’Brien said that there’s considerable excitement around new molecules that are noncovalent BTK inhibitors; specifically, ARQ 531 and LOXO-305.

“All of the BTK inhibitors that we have approved in CLL so far bind in the same ATP binding site, and they are irreversible inhibitors of BTK. So you have to have resynthesis of the BTK in order to escape the drug,” she explained. “In patients who develop clinical resistance, the majority of them will have mutations in that binding site…but the key to the noncovalent inhibitors is that they bind in a different binding site. And so, they are effective, both in the wild-type and also in this setting where you have these resistance mutations.”

In a phase 1 dose-escalation trial of ARQ 531 in patients with relapsed or refractory B-cell lymphoid malignancies, 10 of 40 patients achieved a partial response with higher doses of the treatment. Seven of these patients had relapsed/refractory CLL. The agent was also shown to have a manageable safety profile, with the most common treatment-emergent adverse events being nausea, diarrhea, fatigue, neutrophil count decrease, dysgeusia, and rash.13

In the phase 1/2 BRUIN trial of patients with pretreated B-cell malignancies, LOXO-305 demonstrated efficacy in patients with CLL and mantle cell lymphoma. Among 8 evaluable patients, all 5 patients with CLL had a partial response, and 2 of 3 patients with mantle cell lymphoma had partial responses. All treatment-emergent adverse events were mild and of grade 1 or 2 in severity.

“This would give us a whole other class of BTK inhibitors that could potentially work in patients who become resistant to currently approved BTK inhibitors,” O’Brien said. “So, this would give us a whole other option for a drug choice, enabling us to potentially save venetoclax and yet have a very effective drug in that setting. So I think that the preliminary data from those trials are really exciting, and that’s a new type of drug that could also be a game changer for this disease.”

With these new agents and other promising combinations emerging, newer approaches are sure to work their way into the frontline and relapsed/refractory settings, providing further options for patients with CLL.

1. NCCN Clinical Practice Guidelines in Oncology: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Version 4.2020. NCCN. December 20, 2019. Accessed August 26, 2020. 

https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf

2. Fischer K, Bahlo J, Fink AM, et al. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. 

 2016;127(2):208-215. doi:10.1182/blood-2015-06-651125

3. Thompson PA, Tam CS, O’Brien SM, et al. Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in 

. 2016;127(3):303-309. doi:10.1182/blood-2015-09-667675

4. Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. 

. 2019;381:432-443. doi:10.1056/NEJMoa1817073

5. Burger JA, Tedeschi A, Barr PM, et al; RESONATE-2 investigators. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. 

. 2015;373:2425-2437. doi:10.1056/NEJMoa1509388

6. 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. 

 2020;34:787-798. doi:10.1038/s41375-019-0602-x

7. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. 

 2020;395(10232):1278-1291. doi:10.1016/S0140-6736(20)30262-2

8. Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. 

. 2019;380:2225-2236. doi:10.1056/NEJMoa1815281

9. Al-Sawaf O, Zhang C, Tandon M, et al. Fixed-duration venetoclax-obinutuzumab for previously untreated patients with chronic lymphocytic leukemia: Follow-up of efficacy and safety results from the multicenter, open-label, randomized, phase III CLL14 trial. 

 2020;38(suppl 15):8027. doi:10.1200/JCO.2020.38.15_suppl.8027

10. Jain N, Keating M, Thompson P, et al. Ibrutinib and venetoclax for first-line treatment of CLL. 

. 2019;380:2095-2103. doi:10.1056/NEJMoa1900574

11. Tam CS, Siddiqi T, Allan JN, et al. Ibrutinib (Ibr) plus venetoclax (ven) for first-line treatment of chronic lymphocytic leukemia (cll)/small lymphocytic lymphoma (sll): results from the MRD cohort of the phase 2 CAPTIVATE study. 

 2019;134(suppl 1):35. doi:10.1182/blood-2019-121424

12. Jain N, Keating M, Thompson P, et al. Ibrutinib and venetoclax for first-line treatment of CLL. 

. 2019;380(22):2095-2103. doi:10.1056/NEJMoa1900574

13. Woyach J, Stephens DM, Flinn IW, et al. Final results of phase 1, dose escalation study evaluating ARQ 531 in patients with relapsed or refractory B-cell lymphoid malignancies. 

 2019;134(suppl 1):4298. doi:10.1182/blood-2019-127260

14. 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. 

 2019;134(suppl 1):501. doi:10.1182/blood-2019-127509

Traditional frontline chemoimmunotherapy regimens used to be the gold standard for treating patients with newly diagnosed chronic lymphocytic leukemia. However, over time, targeted therapies have been inching out the use of chemoimmunotherapy to become the preferred approach in this setting.




Author | Lisa Astor

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