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Immunotherapies approved by the FDA in the past decade have become standard of care for many malignancies. Despite the ability of these agents to slow or eradicate numerous tumors, even those metastasized to the brain,

 none thus far have extended survival in glioblastoma (GBM). Given the current lack of positive phase 3 immunotherapy trials for GBM, a misconception held by oncologists and neuro-oncologists is that immunotherapy has no place in this malignancy. In reality, tumor immunology is far too complex to determine infeasibility based on these initial completed trials. In fact, these negative trials provide valuable lessons on designs of future trials based on the hurdles limiting anti-GBM immune responses (

Clinicians treating patients with GBM are crucial to the future of immunotherapy development. Patients must continue to be enrolled into we newer generations of trials that build on past lessons by testing novel therapeutics, combinations, and longitudinal biomarker analyses.

Antagonism of T-cell immune checkpoint molecules PD-1, PD-L1, and CTLA4 unleashes immune responses against many tumors. The remarkable efficacy of antibodies blocking these checkpoints has brought immunotherapy to thousands of patients.

 Three recently completed randomized phase 3 trials in GBM—CheckMate 143 (NCT02017717),

—tested PD-1 blockade, but each demonstrated an objective response rate of less than 10%.

CheckMate 143 evaluated the anti–PD-1 monoclonal antibody nivolumab (Opdivo) in patients with a first recurrence of GBM.

 CheckMate 498 tested radiation and nivolumab vs radiation with standard-of-care temozolomide (Temodar) in patients with newly diagnosed GBM with an unmethylated 

 CheckMate 548 tested the addition of nivolumab to radiation and temozolomide in newly diagnosed patients with a methylated 

 These well-designed trials demonstrated that anti–PD-1 therapy lacks efficacy as a single agent or in combination with standard-of-care therapy for patients with recurrent or newly diagnosed GBM. Importantly, tumors responsive to anti–PD-1 in CheckMate 548 expressed more than 5% PD-L1.

 Therefore, inhibition of local glioblastoma-reactive T cells via PD-L1 is a rare mechanism of immune suppression (Figure). Low PD-L1 expression characterizes immunologically “cold” tumors such as GBM, which is further reflected by a low mutational burden, relatively fewer neoepitopes for T cells, heterogeneity in antigen expression, and a paucity of T cells infiltrating the tumor bed (

Trials moving forward in GBM are attempting to address the lessons learned from the negative phase 3 trials with new checkpoint combinations, timings, and agents targeting multiple antigens. Dozens of other T-cell checkpoints have been identified, many of which are being tested in novel combinations. Examples of these trials include urelumab (antiLAG3) with nivolumab (anti–PD-1; NCT02658981); sabatolimab (anti–TIM-3) with spartalizumab (anti–PD-1) and radiosurgery (NCT03961971); and domvanalimab (anti-TIGIT) with zimberelimab (anti–PD-1; NCT04656535).

These agents potentially modulate T cells in the periphery or in the tumor, with the potential for synergy with radiation or surgery to release tumor antigens and increase T-cell proliferation. Some neoadjuvant or window-of-opportunity trials include surgical resection of recurrent tumor among patients who do or do not receive a preoperative dose of experimental immunotherapy; therefore, pharmacodynamic measures of intratumoral or systemic immune activation can be compared between responders and nonresponders (NCT04656535 and NCT04606316). Clinical trials are increasingly available using novel combinations of immune checkpoint blocking antibodies separately or in combination with standard therapies for patients with recurrent GBM.

Vaccination strategies have been attempted in GBM for many years. Prior strategies failed to encompass the heterogeneity in antigen expression

 or expand enough T cells into the tumor.

 Three ongoing trials employ novel strategies to vaccinate against more potent GBM antigens in combination with immune checkpoint blockade to assist with initial expansion

 in addition to cytolytic activity of T cells.

The multicenter, multinational ROSALIE study (NCT04116658) combines pools of peptides derived from GBM that resemble peptides from the gut microbiome, with the rationale that T cells reactive to these peptides are already relatively prevalent because of prior expansion and activation physiologically in the gut, and thus they could be capable of enhanced tumor killing. This multipeptide vaccine is combined with the anti–PD-1 nivolumab for patients with recurrent glioblastoma with or without the anti–VEGF-A agent bevacizumab (Avastin). Another trial (NCT03491683) incorporates a novel DNA plasmid approach that vaccinates against 3 GBM-associated antigens and adds IL-12 in combination with the anti–PD-1, cemiplimab-rwlc (Libtayo). This regimen is added to chemoradiation with temozolomide for patients with newly diagnosed GBM. Another example includes a personalized neoantigen peptide vaccination strategy in combination with the anti–PD-1 antibody pembrolizumab (Keytruda) plus standard-of-care therapy for patients with newly diagnosed GBM (NCT02287428). Of note, this trial is further evaluating the timing of PD-1 blockade relative to vaccine priming based on emerging data implicating PD-1 signaling on T-cell priming and memory responses.

Clinical trials using other approaches to address the hurdles of intratumoral heterogeneity and other immune suppressive cells as well as factors in the GBM microenvironment (

) are also in development. For example, chimeric antigen receptor (CAR)-positive T cells, which show evidence of efficacy in select patients,

 are being engineered to target more than 1 antigen to account for heterogeneity in GBM.

 Along these lines, City of Hope in Duarte, California, is preparing to launch a trial in which CAR T cells engineered against 2 distinct tumor antigens are coadministered. Such approaches may help overcome therapeutic limitations associated with intratumoral heterogeneity and antigen escape by providing supraphysiologic expansion of distinct tumor-targeting T cells ex vivo that are infused into the tumor or ventricular space.

In addition, oncolytic viral therapy remains an attractive approach for reversing the poorly understood complexities of the tumor microenvironment, which likely arise in great part from myeloid and other prevalent cell populations in GBM.

 Oncolytic viruses induce proinflammatory changes in the microenvironment by introducing of viral proteins and nucleic acids and lysis-mediated release of powerful danger signals, in addition to releasing GBM antigens in the microenvironment. Combinations of oncolytic virus and immune checkpoint blockade now seek to potentiate T-cell responses to glioblastoma antigens,

 including some trials incorporating serial, longitudinal oncolytic virus injection

 (NCT03636477; NCT02798406; NCT03152318). Although specific mechanisms of immune suppression in the GBM microenvironment are being elucidated, oncolytic viral therapy represents a promising approach to potentially reverse this immensely complex problem.

Single agent blockade of PD-1 has failed to extend survival in patients with GBM as it has in other cancers. However, advances in our understanding of the key hurdles to immune-mediated tumor killing are informing the current generation of clinical trials using rational combinations. Patients in clinical trials contribute to the understanding of immune suppression in this disease through immune monitoring. Given the complexity of the immune system and an equally complex set of mechanisms for therapeutic targeting, the current landscape of trials is only the beginning of the story of immunotherapy for GBM.

David A. Reardon, MD, is clinical director of the Center for Neuro-Oncology and institute physician at Dana-Farber Cancer Institute, and a professor of medicine at Harvard Medical School, both in Boston, Massachusetts. 

Brian M. Andersen, MD, PhD, is an instructor in neurology in the Department of Neurology at Brigham and Women’s Hospital, Harvard Medical School, in Boston, Massachusetts, and in the Department of Neurology at Veterans Affairs Medical Center in Jamaica Plain, Massachusetts.

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Articles

Given the current lack of positive phase 3 immunotherapy trials for glioblastoma, a misconception held by oncologists and neuro-oncologists is that immunotherapy has no place in this malignancy. 

Will Immunotherapy Become a Standard of Care for Glioblastoma?

Despite incremental advances in the treatment landscape of metastatic colorectal cancer (mCRC), patients with the disease still face a poor prognosis. The 5-year survival rate of approximately 14% underscores the need for more effective therapeutics in the space,1 but the recent emergence of XL092, a novel tyrosine kinase inhibitor (TKI), has sparked hope that the agent could become a key part of the mCRC treatment armamentarium.

“Most patients with mCRC will die from their disease; they [generally] don’t die from something else first,” J. Randolph Hecht, MD, director of the UCLA Gastrointestinal Oncology Program and a professor of clinical medicine at the David Geffen School of Medicine at UCLA in Los Angeles, California, told 

. “Unfortunately, we have not moved the bar, really, in more than a decade. Fluorouracil was synthesized in the 1950s and was approved in 1962. Oxaliplatin and irinotecan come from the late 1990s. VEGF inhibitors are from the early 2000s, [followed by] EGFR [inhibitors]. We have had minor improvements since that time. Regorafenib [Stivarga] has some modest benefit. [There is also] trifluridine/tipiracil; there was just recently a phase 3 trial showing some modest benefit adding bevacizumab [Avastin] to that, but we’re talking benefits in months.”

XL092 has multiple targets, including MET, VEGFR2, and TAM kinases, which have been shown to stimulate tumor growth, metastasis, angiogenesis, and immune suppression of the tumor microenvironment.2 The agent was also engineered to have a short half-life of approximately 21 hours, which enables it to be administered via daily dosing and adds to its manageable tolerability profile. Additionally, previous phase 1/2 trials have shown that VEGFR2 TKIs can be effective in mCRC that is not microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) when combined with immune checkpoint inhibitors.

XL092 Shows Promise in Early-Phase Study 

Building off preclinical findings, XL092 has displayed preliminary efficacy with a manageable safety profile, both as a monotherapy and in combination with the immune checkpoint inhibitor atezolizumab (Tecentriq) targeting PD-L1 in patients with advanced solid tumors in the ongoing phase 1 STELLAR-001 trial (NCT03845166).

STELLAR-001 is a dose-escalation and expansion study that is enrolling adult patients with an ECOG performance status of 1 or 0. As of June 13, 2022, 47 patients have been treated with XL092 monotherapy and 40 have received the combination regimen. 

In the monotherapy cohort, daily oral XL092 was given at doses of 10 mg (n = 3), 20 mg (n = 7), 40 mg (n = 6), 80 mg (n = 5), 100 mg (n = 5), 120 mg (n = 14), and 140 mg (n = 7). Doses at the 10-mg and 20-mg levels were administered in powder form, and all higher doses were via tablet.

In the combination arm, patients were treated with XL092 40 mg (n = 3), 80 mg (n = 16), 100 mg (n = 14), and 120 mg (n = 7), via daily oral administration. Atezolizumab 1200 mg was given intravenously every 3 weeks.

The dose-limiting toxicity (DLT) evaluation period was days 1 through 28 for the monotherapy cohort and days 1 through 21 for the combination cohort. In the monotherapy arm, safety was assessed on day 1 of the first 4 weeks, with additional assessments on day 2 of week 1, day 7 of week 4, day 1 of week 6, day 1 of week 9, and then every 4 weeks thereafter. In the combination arm, safety was assessed on day 1 of the first 4 weeks, with additional assessments on day 2 of week 2, day 7 of week 3, and then every 3 weeks thereafter.

Patients had a median age of 61 years (range, 19-79) and 59 years (range, 24-82) in the monotherapy and combination arms, respectively. Most patients in both arms were White (81% and 73%, respectively), had an ECOG performance status of 1 (62% and 55%), and had previously undergone at least 3 lines of systemic anticancer therapy (68% and 68%). Three patients in the monotherapy arm had a diagnosis of CRC, compared with 7 in the combination arm.

The primary end point was to determine the maximum-tolerated dose (MTD) and/or the recommended dose of XL092 alone and in combination with atezolizumab. Secondary end points included assessing safety, tolerability, and plasma pharmacokinetics. Overall response rate (ORR) per RECIST 1.1 and other efficacy measures served as exploratory end points.

Safety findings from the trial showed that at a median follow-up of 17.9 months (range, 4.6-38.8), 20 patients in the monotherapy arm experienced dose reductions of XL092 and 9 patients discontinued treatment with the agent due to treatment-emergent adverse effects (TEAEs). Treatment-related adverse effects (TRAEs) led to discontinuation in 7 patients. DLTs were observed in 2 patients, and 14 remained on study treatment at the data cutoff.

In the combination arm, at a median follow-up of 6 months (range, 0.2-20.0), TEAEs leading to dose reductions of XL092 were observed in 9 patients. Eight patients discontinued treatment due to TEAEs, and 3 patients discontinued treatment due to TRAEs. Atezolizumab was discontinued due to TEAEs and TRAEs in 7 and 3 patients, respectively. DLTs were present in 3 patients.

The 2 DLTs in the monotherapy arm both occurred at the 140-mg dose level (grade 3 hypertension and grade 3 diarrhea). In the combination arm, DLTs were present at 3 different dose levels: 80 mg (grade 2 fatigue), 100 mg (grade 3 gastritis), and 120 mg (grade 3 abdominal pain). No grade 5 TRAEs were reported in either arm. 

All patients in the monotherapy arm experienced an any grade TEAE, including nausea (51%), hypertension (45%), diarrhea (43%), and fatigue (36%). Grade 3/4 TEAEs were reported in 60% of patients and included hypertension (19%), diarrhea (9%), fatigue (6%), and vomiting (2%).

Similarly in the combination arm, nearly all patients (98%) experienced a TEAE of any grade, including fatigue (63%), diarrhea (48%), decreased appetite (43%), and hypertension (25%). Grade 3/4 TEAEs occurred in fewer patients compared with the monotherapy arm (38% vs 60%), and included hypertension (13%), thrombocytopenia (5%), and abdominal pain (5%).

Preliminary efficacy findings showed that XL092 displayed antitumor activity as both monotherapy and as a component of the combination. Overall, the ORRs were 10% (95% CI, 2.7%-23.1%) and 4% (95% CI, 0.1%-19.0%), respectively. Moreover, the disease control rates were 90% (95% CI, 76.9%-97.3%) and 74% (95% CI, 53.7%-88.9%), respectively. Tumor reduction was observed in 71% and 56% of patients, respectively. 

“XL092 in combination with PD-L1 pathway inhibitors showed the patients actually had responses [even though] we would expect not to see any responses or very small number of responses,” Hecht said. “Now there are lots of potential reasons for this, [one of which] may be what they’re inhibiting. All those [kinases] have to do with immunosuppression. That’s the theoretical reason for this.” 

Investigators determined the MTD of XL092 to be 120 mg and the recommended dose to be 100 mg for the agent both as monotherapy and in combination with atezolizumab. The 100-mg dose was chosen based on the manageable toxicity profile, best overall response data, and plasma biomarker data suggesting a consistent peripheral pharmacodynamic effect.

Pivotal STELLAR-303 Trial Looks to Validate Preliminary Findings 

Following the positive preclinical and earlyphase findings displayed by XL092, investigators are initiating the phase 3, global, open-label STELLAR-303 trial (NCT05425940).

 Exelixis, the developer of XL092, cited promising outcomes observed with cabozantinib (Cabometyx) in combination with immunotherapies, such as atezolizumab in the phase 1b COSMIC-021 trial (NCT03170960), which supported the investigation.

Among 31 patients with CRC in the multicohort study, the objective response rate was 10%, with a disease control rate of 71% and median duration of response of 7.6 months (95% CI, 4.2-not estimable). Further, the combination elicited a median progression- free survival (PFS) of 3.0 months (95% CI, 2.7-5.4) and a median overall survival (OS) of 14.0 months (95% CI, 5.5-16.7).

 mutational status also was evaluated in the study as an exploratory end point, and 12 patients with RAS wild-type disease drove the outcomes. The ORR for those with 

 wildtype disease vs those without (n = 19) was 25% vs 0%, respectively. This advantage extended to PFS and OS outcomes. The median PFS was 5.8 months (95% CI, 2.8-11.0) vs 2.7 months (95% CI, 1.6-4.1), respectively, with a median OS of 16.7 months (95% CI, 8.4-NE) compared with 8.7 months (95% CI, 4.7-15.9), respectively.

“These small molecules [TKIs] all block other kinases—sometimes they’re called multitargeted—and some of those kinases may actually have to do with immune suppression,” Hecht said. “There’s been a thought that perhaps combining these drugs together might finally kind of crack the code and get long-term responses, or even any responses at all, in this huge group of patients.” 

STELLAR-303 has an estimated enrollment of approximately 600 adult patients with RAS wild-type or RAS-mutant mCRC. Investigators want to include approximately 400 patients with 

 wild-type disease and 200 patients with 

-mutant disease. The trial will compare the safety and efficacy of XL092 in combination with atezolizumab with that of the multikinase inhibitor regorafenib.

To be eligible for enrollment, patients must have measurable disease per RECIST 1.1 and an ECOG performance status of 1 or 0. Patients need to have experienced radiographic progression on, be refractory to, or be intolerant to standard-of-care therapy for mCRC. Additionally, progression must have occurred during treatment or within 3 months of receiving the most recent standard-of-care therapy. Patients with MSI-H/dMMR disease will be excluded. 

After enrollment, patients will be randomly assigned 1:1 to receive either oral XL092 100 mg daily in combination with intravenous atezolizumab 1200 mg once every 3 weeks or oral regorafenib 160 mg daily for the first 21 days of each 28-day cycle (FIGURE).

 Patients will be stratified by geographic region (Asia vs other), RAS status (wild-type vs mutant), and the presence of liver metastases (yes vs no). 

“In some of the early trials, there was a correlation between being RAS wild-type—that’s approximately 50% of colorectal cancers—and better response. STELLAR-303 builds on those trials,” Hecht said. Tumor assessment per RECIST 1.1 will be performed every 8 weeks through week 49, then once every 12 weeks thereafter. Patients will receive study treatment until intolerable toxicity or lack of clinical benefit is reported. 

The primary end point is overall survival (OS) in the 

 Secondary end points include PFS, ORR, duration of response, OS, and safety. Recruitment for STELLAR-303 began in June 2022 and is ongoing.

 The study is estimated to be completed in February 2026.

Survival rates for colorectal cancer. American Cancer Society. Updated March 1, 2022. Accessed February 10, 2023. bit.ly/3jwaKZQ

Hecht JR, Tabernero J, Parikh AR, et al. STELLAR-303: a phase 3 study of XL092 in combination with atezolizumab versus regorafenib in patients with previously treated metastatic colorectal cancer (mCRC). 

. 2023;41(suppl 4):TPS267. doi:10.1200/JCO.2023.41.4_suppl.TPS267

Sharma MR, Subbiah V, Shapiro G, et al. A phase I first-in-human study of XL092 in patients (pts) with locally advanced or metastatic solid tumors: results from dose-escalation of XL092 alone and in combination with atezolizumab. 

. 2022;33(suppl 7):S760. doi:10.1016/j.annonc.2022.07.609

Study of XL092 + atezolizumab vs regorafenib in subjects with metastatic colorectal cancer (STELLAR-303). ClinicalTrials.gov. Updated January 6, 2023. Accessed February 10, 2023. https://www.clinicaltrials.gov/ct2/show/NCT05425940

Exelixis announces initiation of the STELLAR-303 phase 3 pivotal trial evaluating XL092 in patients with metastatic colorectal cancer. News release. Exelixis Inc. June 21, 2022. Accessed February 10, 2023. bit.ly/3XlJZ8i

Abrams TA, Kazmi SMA, Winer IS, et al. A phase 1b multitumor cohort study of cabozantinib plus atezolizumab in advanced solid tumors (COSMIC-021): results of the colorectal cancer cohort. 

. 2022;40(suppl 4):121. doi:10.1200/JCO.2022.40.4_suppl.121

Oncology Live®

Despite incremental advances in the treatment landscape of metastatic colorectal cancer, patients with the disease still face a poor prognosis. 

STELLAR-303 Aims to Carve Out Space for XL092 in mCRC Treatment Paradigm

Most members of the BET protein family are ubiquitously expressed in human tissues and play an important role in epigenetic regulation of gene transcription and cell-cycle progression.

 BET proteins are commonly dysregulated in human malignancies, which leads to abnormal expression of oncogenes. An understanding of these processes has prompted investigators to explore the idea of these proteins as a therapeutic target for cancer.

Monotherapy with first-generation BET inhibitors was largely unsuccessful in clinical contexts because of dose-limiting toxicities (DLTs), particularly thrombocytopenia, that prevented escalation to a dose that would completely inhibit the target.

 However, development of rational therapeutic combinations that include BET inhibitors may deliver a synergistic antitumor effect and enable safe and effective use in the clinical setting.

 Investigators are testing a new crop of novel BET inhibitors as monotherapy and in combinations, particularly in hematologic malignancies (

Role of BET Pathway Proteins in Healthy and Malignant Cells

In a variety of contexts, the proteins BRD2, BRD3, and BRD4 are upregulated or abnormally expressed in activated immune cells, where they tend to exert proinflammatory effects.

 Another member of the BET family, BRDT, is primarily found in germ cells.

Of the BET proteins, BRD4 has particularly abundant levels. Numerous stimuli cause elevated BRD4 expression in various resident immune cells, leading to increased transcriptional activation of immune and inflammatory genes.

 BRD4 may act as a stress protein. For example, it is upregulated in the uterus and fetal membranes during labor and infection, as well as in the placenta during severe early-onset preeclampsia.

BRD2 expression is high in pancreatic ß cells, where it has been shown to interfere with mitosis and insulin transcription; induction of BRΔ2 expression also triggers the neuroinflammation associated with Parkinson disease.

BRD3 expression is upregulated in activated lymphocytes, suggesting its involvement in the development of adaptive immunity, and has been found in macrophages in synovial tissue from individuals with rheumatoid arthritis and osteoarthritis.

BRD2, BRD3, and BRD4 also have been shown to exert effects without changes in their expression. Further studies are needed to elucidate the mechanisms regulating the expression of BET proteins and the relationship between these proteins’ expression and function in various clinical settings.

BET proteins also mediate changes in histone acetylation that can lead to development of cancer.

 BET proteins have been linked to abnormal expression of the MYC oncogene in mixed-lineage leukemia, acute myeloid leukemia (AML), Burkitt lymphoma, and Burkitt-like lymphoma.

BET family proteins also can form oncogenic fusion proteins, such as the in-frame fusion of BRD and NUT, which is a key driver of NUT midline carcinoma.

Interactions between BET proteins and nuclear factor κB (NF-κB), a proinflammatory, heterodimeric transcription factor, also contribute to cancer, and BRD2 and BRD4 are involved in constitutive activation of NF-κB in models of activated B-cell diffuse large B-cell lymphoma.

Because of the role of BET proteins in the development of many tumor types, inhibition of BET has been proposed as an antitumor strategy for the treatment of numerous solid tumors and hematologic malignancies.

Additionally, BET inhibitors appear to target tumor cells over normal cells selectively because they bind preferentially to superenhancers, or noncoding DNA regions bound by multiple transcription factors that help determine cellular identity.

 Several BET inhibitors have been studied as monotherapy in early-stage clinical trials, although multiple DLTs, including thrombocytopenia, gastrointestinal and testicular toxicities, neutropenia, anemia, dysgeusia, and fatigue, precluded escalation to a dose that would be sufficient for adequate target inhibition.

 Therefore, strategies combining agents that act synergistically with BET inhibitors may be more successful as anticancer therapies and have shown promise in early-stage clinical trials.

Pelabresib (CPI-0610) is an investigational, orally administered, small molecule BET inhibitor that reduces expression of BET target genes and modulates NF-κB signaling.

 Analysis of preliminary data from the open-label, phase 1/2 MANIFEST study (NCT02158858) of patients with myelofibrosis found that pelabresib plus ruxolitinib (Jakafi), a JAK1/2 inhibitor, led to a 35% or greater reduction in spleen volume (SVR35) in 68% (57 of 84) and a 50% or greater reduction in total symptom score (TSS50) at week 24 in 56% (46 of 82) of patients with JAK inhibitor–naïve disease (arm 3).

 SVR35 was achieved by 20% (16 of 81) and TSS50 occurred in 37% (30 of 81) of patients with myelofibrosis who previously had a suboptimal response to ruxolitinib (arm 2).

 Thrombocytopenia was the most common hematologic treatment-emergent adverse event (TEAE) in arm 3 (any grade, 52%; grade ≥ 3, 12%) and arm 2 (any grade, 52%; grade ≥ 3, 33%).

 Anemia was reported in 42% (grade ≥ 3, 35%) and 27% (grade ≥ 3, 19%) of patients in arm 3 and arm 2, respectively.

Although low-grade gastrointestinal TEAEs and respiratory infections occurred, they rarely required discontinuation of treatment.

 Based on the findings in arm 3, the global phase 3 MANIFEST-2 trial (NCT04603495) was developed and is randomly assigning patients with JAK inhibitor–naïve myelofibrosis to receive pelabresib plus ruxolitinib or ruxolitinib alone (N = 200 per arm).

 SVR35 response and TSS50 response at week 24 are the primary and key secondary end points, respectively.

BMS-986158 Plus Ruxolitinib or Fedratinib

BMS-986158 is an orally administered, potent, and selective small molecule BET inhibitor that has a dose-proportional pharmacokinetic profile and modulates BET target gene expression in a dose-dependent manner.

 Concomitant inhibition of BET-mediated and JAK/STAT pathways has additional therapeutic benefits over BET-targeted inhibition alone in patients with myelofibrosis.

The phase 1/2 CA011-023 study (NCT04817007) includes a dose-escalation phase of BMS-986158 plus ruxolitinib in patients with myelofibrosis and no prior exposure to ruxolitinib (part 1A) or BMS-986158 plus fedratinib (Inrebic) in patients with myelofibrosis previously treated with ruxolitinib (part 1B). The study also includes a dose-expansion phase at the recommended phase 2 dose of BMS-986158 plus ruxolitinib (part 2A), BMS-986158 in combination with ruxolitinib (part 2A), or BMS-986158 with or without fedratinib (part 2B).

A report of initial safety and efficacy data from parts 1A (n = 11) and 1B (n = 12) presented at the 2022 American Society of Hematology (ASH) Annual Meeting showed that DLTs occurred in 2 patients in part 1A (both thrombocytopenia) and 3 patients in part 1B (diarrhea, thrombocytopenia, and elevated bilirubin).

 All patients in part 1A remained on treatment, whereas 2 patients in part 1B discontinued treatment because of TEAEs (thrombocytopenia and elevated bilirubin).

In part 1A, 5 of 6 evaluable patients (83%) achieved SVR35 at 12 weeks (mean SV change, −50.3%; SD, 14.5), and all 6 patients (100%) achieved SVR35 at 24 weeks (mean SV change, −56.8%; SD, 9.7).

 In part 1B, none of the 6 evaluable patients achieved SVR35 at 12 weeks (mean SV change, −9.9%; SD, 11.4) and only 1 of the 3 remaining evaluable patients achieved SVR35 at 24 weeks (mean SV change, −32.7%; SD, 11.2).

The authors concluded that BMS-986158 combined with ruxolitinib or fedratinib had a manageable safety profile, and that the combination of BMS-986158 plus ruxolitinib led to a considerable reduction in SV that continued to deepen between 12 and 24 weeks of treatment in ruxolitinib-naïve patients.

ZEN-3694 is an orally administered, second-generation pan-BET inhibitor that reduces expression of androgen receptor (AR) signaling genes, AR splice variants, 

, glucocorticoid receptor, and other oncogenes and has shown synergistic activity with enzalutamide (Xtandi), an AR inhibitor, in models of castration-resistant prostate cancer (CRPC).

 A first-in-human, phase 1b/2 trial (NCT02711956) evaluated the safety and efficacy of ZEN-3694 plus enzalutamide in 75 patients with metastatic CRPC and prior progression on at least 1 androgen signaling inhibitor.

 Grade 3 or higher TEAEs were observed in 18.7% of patients, with nausea (4%), thrombocytopenia (4%), anemia (2.7%), fatigue (2.7%), and hypophosphatemia (2.7%) most commonly reported.

 The most common any-grade AEs attributed to ZEN-3694 were visual disturbances (67%), nausea (45%), fatigue (40%), decreased appetite (25%), dysgeusia (20%), thrombocytopenia (15%), and decrease in body weight (11%).8 Dose reductions or treatment discontinuation due to AEs were needed in 32% of patients, with gastrointestinal toxicities accounting for 83% of discontinuations and dose reductions.

Pharmacodynamic analysis showed dose-dependent decreases in whole-blood mRNA levels of several BET inhibitor target genes, and the mean radiographic progression-free survival (rPFS) was 9.0 months (95% CI, 4.6-12.9).

 The on-treatment median rPFS was 10.6 months (95% CI, 7.5-not reached) among the subset of 12 patients with primary resistance to first-line AR-targeted therapy.

These findings prompted the initiation of an open-label, randomized phase 2b trial (NCT04986423), which is comparing ZEN-3694 plus enzalutamide with enzalutamide alone in 2 cohorts of patients with metastatic CRPC who have progressed on abiraterone acetate (Zytiga), an antiandrogen therapy.

 Cohort A (n = 150) includes patients who had a poor response to abiraterone, and cohort B (n = 50) consists of patients who responded to abiraterone.

 The primary end point is rPFS by blinded independent central review in cohort A evaluated by Prostate Cancer Clinical Trials Working Group 3 consensus for trials in CRPC.

 The study, which seeks to enroll 200 participants, was launched in September 2021 and has an estimated primary completion date of March 2024.

ZEN-3694 also has been shown to decrease mRNA levels of multiple genes involved in DNA repair, thus increasing sensitization of PARP inhibitor–resistant breast cancers to PARP inhibitors.

 Although PARP inhibitors typically are administered only to patients with breast cancer with germline 

 mutations, ZEN-3694 is believed to be effective in 

A phase 1b/2 trial (NCT03901469) evaluated ZEN-3694 in combination with the PARP inhibitor talazoparib (Talzenna) in 52 patients with triple-negative breast cancer (TNBC) without germline 

 mutations, and results were presented at the 2022 American Society of Clinical Oncology Annual Meeting.

Thrombocytopenia was the most common AE (any grade, 55%; grade ≥ 3, 34%), although this was ameliorated with dose holds and reductions.

 Assessment of BET-dependent and homologous recombination repair transcripts in paired tumor biopsies taken before and after treatment revealed robust engagement of target DNA repair genes on treatment.

In the phase 2 portion of the trial, the clinical benefit rate, defined as objective response rate (ORR) plus stable disease for more than 16 weeks, was 30% (11 of 37 patients), which met that phase’s primary end point.

 For the entire phase 1b/2 trial, the investigator-assessed ORR was 22% (11 of 50 patients, including 2 complete responses), the clinical benefit rate was 35% (18 of 51), and median duration of response was 24 weeks.

Notably, all the confirmed responses occurred in the subset of 34 patients with TNBC at diagnosis (ie, no history of hormone receptor–positive disease), consistent with the expectation that TNBC tumors would be more sensitive to the combination because of their basal-like properties.

 The trial has been expanded to phase 2b, in which enrollment of an additional 80 patients with TNBC at diagnosis is planned.

PLX51107 is a BET inhibitor with a novel binding site in the acetylated lysine-binding pocket of BRD4, which exerts effects on gene transcription.

 PLX51107 showed antitumor effects in in vitro and in vivo models of AML; however, extended exposure to BET inhibition can lead to resistance mediated by increased activation of the canonical ß-catenin–dependent Wnt signaling pathway.

PLX51107 may exert synergistic activity with dinaciclib, a multi-CDK inhibitor, and reverse resistance to BET inhibition by inhibiting Wnt signaling.

 Results of a preclinical study presented at the 2022 ASH Annual Meeting showed that PLX51107 and dinaciclib had synergistic activity in AML cell lines, as demonstrated by a decrease in mitochondrial activity.

 Additionally, dinaciclib downregulated Wnt/ß-catenin signaling in AML cell lines, and sensitivity to dinaciclib was similar in PLX51107-resistant and -sensitive cells.

The combination of PLX51107 and dinaciclib also demonstrated synergy in a xenograft mouse model of AML. In addition to decreased disease burden, mice that received the combination had significantly longer median overall survival than those that received PLX51107 alone or vehicle treatment (57 days with combination vs 42 days with PLX51107 and 28 days with vehicle treatment; 

 < .05); dinaciclib alone did not improve survival compared with vehicle treatment.

 The authors concluded that these data support the addition of a multi-CDK inhibitor as a potential strategy for thwarting resistance to BET-targeted agents in AML.

Inhibition of BET has emerged as a promising anticancer strategy in several tumor types, and development of rational therapeutic combinations may allow clinical benefits to be achieved from BET inhibitors at tolerable doses.

 Development of more selective BET inhibitors such as agents that selectively target the BD1 or BD2 domain on all 4 BET proteins or that target specific BRDs, targeted delivery approaches such as antibody-drug conjugates, or therapies that selectively degrade BRDs may be other strategies to maintain or improve efficacy of BET inhibitors while reducing hematologic toxicity.

Trojer P. Targeting BET bromodomains in cancer. 

. 2022;6:313-336. doi:10.1146/annurev-cancerbio-070120-103531

Wang N, Wu R, Tang D, Kang R. The BET family in immunity and disease. 

. 2021;6(1):23. doi:10.1038/s41392-020-00384-4

Alqahtani A, Choucair K, Ashraf M, et al. Bromodomain and extra-terminal motif inhibitors: a review of preclinical and clinical advances in cancer therapy. 

. 2019;5(3):FSO372. doi:10.4155/fsoa-2018-0115

Doroshow DB, Eder JP, LoRusso PM. BET inhibitors: a novel epigenetic approach. 

. 2017;28(8):1776-1787. doi:10.1093/annonc/mdx157

Mascarenhas J, Kremyanskaya M, Patriarca A, et al. BET inhibitor pelabresib (CPI-0610) combined with ruxolitinib in patients with myelofibrosis—JAK inhibitor-naïve or with suboptimal response to ruxolitinib—preliminary data from the MANIFEST study. 

. 2022;6:99-100. doi:10.1097/01.HS9.0000843684.97625.7e

Harrison C, Rampal RK, Gupta V, et al. MANIFEST-2, A global, phase 3, randomized, double-blind, active-control study of pelabresib (CPI-0610) and ruxolitinib vs placebo and ruxolitinib in JAK inhibitor-naïve myelofibrosis patients. 

An understanding of BET protein dysregulation, which leads to abnormal expression of oncogenes, has prompted investigators to explore the idea of these proteins as a therapeutic target for cancer.

Vol. 24/No. 5 | Oncology Live®

Will Immunotherapy Become a Standard of Care for Glioblastoma?

STELLAR-303 Aims to Carve Out Space for XL092 in mCRC Treatment Paradigm

BET Inhibitors in Cancer Therapy: Finding the Right Combination

New Generation of TKIs Challenge Standards of Care in Newly Diagnosed Ph+ ALL

MDS Options Are Poised to Expand Across Risk Groups

Pragmatic Approaches to Cancer Management in the Absence of Randomized Trial Data