Jessica Hergert

Early-phase date shared during the 2021 Genitourinary Cancers Symposium showed that the investigational agent VERU-111 showed promising activity in patients with metastatic castration-resistant prostate cancer (mCRPC) who had progressed on androgen receptor (AR)–targeted therapy.1

In a phase 1b study, VERU-111 induced a prostate-specific antigen (PSA) decline in 6 of 10 men who received at least four 21-day cycles of continuous dosing with the investigational tubulin inhibitor. Further, PSA declines of ≥30% and ≥50% were achieved by 4 and 2 patients, respectively.

Two men experienced partial responses and 8 men experienced stable disease as best objective tumor response. Two additional objective responses occurred in patients who did not reach 4 cycles of continuous dosing.

The median duration of treatment without progression was greater than 11 months (range, 6.0-22.0). Three men remain on study and have a median duration of treatment without progression of more than 10.5 months (range, 4.2-22+).

“The data from the phase I study showed VERU-111 is safe and well tolerated at continuous daily dosing,” said Mark Christopher Markowski, MD, PhD, lead study author and assistant professor of oncology at Johns Hopkins Medicine. “We are excited to develop an oral therapy for men with metastatic prostate cancer that does not directly target the AR signaling pathway. In the future, VERU-111 may serve as an alternative to intravenous taxane chemotherapies in men with advanced disease.”

VERU-111, a “railroad tracks disruptor” that targets the cytoskeleton, binds to the α and β tubulin subunits of microtubules. Furthermore, the agent targets the colchicine binding site to crosslink these subunits, inhibit microtubule polymerization, and downregulate intermediate filaments of the cytoskeleton.

The agent demonstrated high oral bioavailability in preclinical studies, with a favorable toxicity profile and activity against taxanes, vinca alkaloids, doxorubicin, enzalutamide (Xtandi), and abiraterone acetate (Zytiga)–resistant prostate cancers.

The open-label, phase 1b, dose-escalation portion of the study utilized a 3+3 design. Eligible patients (n = 39) had to have mCRPC and received 1 prior AR-targeted therapy. Additionally, patients who had received up to 1 prior line of taxane-based chemotherapy for mCRPC were included.

In part 1 of the phase 1b trial, patients received oral VERU-111 daily on days 1 through 7 of a 21-day cycle. In part 2, patients who tolerated the 7-day dosing schedule escalated to a 14-day schedule every 21 days. If the 14-day schedule was tolerated, patients escalated to continuous daily dosing of VERU-111 until disease progression or unacceptable toxicity.

Patients (n = 39) were a median age of 74 years (range, 61-92) and had a median sum Gleason score of 8 (range, 5-10). The majority of patients (n = 28; 72%) were Caucasian, and the remainder of patients were African American (n = 8; 21%) or Hispanic (n = 3; 8%).

Over half of patients (n = 21; 54%) had an ECOG performance status (PS) of 0; 41% and 8% had an ECOG PS of 1 and 2, respectively.

Sites of metastatic disease included bone only (n = 21; 55%), lymph node only (n = 6; 16%), bone and lymph node (n = 8; 21%), visceral (n = 1; 3%), and visceral and bone (n = 1; 3%).

Prior therapies included abiraterone (n = 14; 36%), enzalutamide (n = 8; 20%), abiraterone and enzalutamide (n = 17; 44%), and taxane-based chemotherapy (n = 9; 23%).

An efficacy analysis of patients who received the recommended phase 2 dose (RP2D) of 63 mg and were evaluable for efficacy (n = 16) showed that the median duration of treatment without progression was greater than 5.8 months (range, 0-22+). Excluding patients who discontinued treatment because of adverse effects (AEs), the median duration of treatment without progression was great than 9.8 months (range, 2-22+).

Notably, the poster presentation included 2 patient case studies.

The first patient had a Gleason score of 9 and node-only mCRPC. Prior treatments included sipuleucel-T (Provenge), enzalutamide, and abiraterone. The patient remained on study for more than 22 months and experienced a 63% decline in PSA from baseline at initiation of the first 21-day cycle.

A screening CT scan from March 8, 2019 showed a 1.7 cm by 1.5 cm measurable target lesion in the retroperitoneal lymph node. A 15-month follow-up scan completed on June 10, 2020 showed a 33% decrease in size to a nonpathologic node; the tumor shrunk to 1.1 cm by 1.0 cm.

The second case study highlighted a 73-year-old patient who received the 72-mg dose of VERU-111. The patient had bone- and node-positive mCRPC, a Gleason score of 8, and progression on leuprolide acetate (Lupron), sipuleucel-T, enzalutamide, and abiraterone.

At baseline, the patient had a 7 cm by 3.1 cm target lesion in the right obturator lymph node. Subsequent scans showed tumor shrinkage to 7 cm by 2.4 cm at 4 months and 5.4 cm by 2.4 cm at 5 months, representing a best reduction of 23%. Overall, the patient received VERU-111 for 7 months and obtained a 36% decline in PSA from baseline at initiation of the first 21-day cycle.

Regarding safety in the overall dose-escalation cohort, the most common all-grade treatment-related AEs (TRAEs) reported in more than 2 patients across all dosing levels included diarrhea (n = 38), fatigue (n = 24), and nausea (n = 21). Other all-grade TRAEs included anemia (n = 6), anorexia (n = 3), decreased appetite (n = 8), dizziness/lightheadedness (n = 3), dysgeusia (n = 4), elevated alanine transaminase (n = 5), elevated aspartate transaminase (n = 5), hyponatremia (n = 4), neutropenia/neutrophil decrease (n = 5), vomiting (n = 8), and weight loss (n = 8).

Of these TRAEs, grade 3 events included anemia (n = 1), diarrhea (n = 3), fatigue (n = 3), nausea (n = 1), and vomiting (n = 1).

In the 25 patients who received the RP2D of oral VERU-111 for at least 1 cycle, the majority of AEs were grade 1 or 2. All AEs observed included diarrhea (n = 17; 68%), nausea (n = 8; 32%), decreased appetite (n = 5; 20%), constipation (n = 4; 16%), fatigue (n = 4; 16%), vomiting (n = 4; 16%), dysgeusia (n = 3; 12%), weight loss (n = 3; 12%), abdominal cramping (n = 2; 8%), edema in the lower extremity (n = 2; 8%), and low white blood cell count (n = 2; 8%).

All drug-related AEs included diarrhea (n = 14; 56%), nausea (n = 6; 24%), decreased appetite (n = 3; 12%), fatigue (n = 3; 12%), dysgeusia (n = 3; 12%), weight loss, (n = 3; 12%), vomiting (n = 2; 8%), and low white blood cell count (n = 2; 8%).

Additionally, 1 patient experienced a grade 3 or greater, drug-related fatigue at the 63-mg dose. The patient was reduced to a 54-mg dose, and the fatigue resolved.

A phase 2 trial of VERU-111 in patients with mCRPC who are resistant to an AR-targeted agent who have not received prior intravenous chemotherapy is ongoing (NCT03752099).

 Patients will start on 63 mg of continuous, daily VERU-111. If unacceptable toxicity occurs, patients will be reduced to 54 mg of continuous, daily dosing.

The primary end point of the study is radiographic progression-free survival (rPFS). Initial results reported that objective tumor responses have been observed, including a complete response. PSA responses, including PSA declines of more than 50%, have also been observed. Patients have remained on study for more than 9 months, and the safety profile appears similar to that observed in the phase 1b study.

“Our data suggests [that] VERU-111 warrants further study. Enrollment on the phase 2 portion of the study is complete, and we look forward to sharing those results,” Markowski added.

The investigators also reported that a positive meeting with the FDA regarding VERU-111 took place in July 2020. As such, the pivotal phase 3 VERACITY trial is set to launch in early 2021. Because rPFS is set to be the primary end point, the sample size of the phase 3 study could include between 200 and 300 men.

1. Markowski MC, Eisenberger MA, Tutrone RF, et al. Clinical study of VERU-111, an oral cytoskeletal disruptor in men with metastatic castration resistant prostate cancer (mCRPC) who failed an androgen receptor targeting agent. 

. 2021(suppl 6):131. doi:10.1200/JCO.2021.39.6_suppl.131

2. To evaluate safety and tolerability of VERU-111 in men with advanced metastatic castration resistant prostate cancer. ClinicalTrials.gov. Posted November 23, 2018. Updated February 2, 2021. Accessed February 11, 2021. 

https://clinicaltrials.gov/ct2/show/NCT03752099

3. VERU-111. Veru Inc. 2021. Accessed February 11, 2021. 

https://verupharma.com/pipeline/veru-111/

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 The investigational tubulin inhibitor was also safe and well tolerated at continuous daily dosing.

Novel agent VERU-111 active in pretreated prostate cancer

Dual immune checkpoint blockade with the PD-1 inhibitor tislelizumab and the PD-L1 inhibitor BGB-A333 induced an overall response rate (ORR) of 42% in a small study of patients with urothelial carcinoma.

The findings showed that among 12 patients receiving the immunotherapy combination, there were 3 complete responses (CRs), and 2 partial responses (PRs). Another 4 patients achieved table disease, with 2 patients having progressive disease, and 1 patient not being evaluable. The median duration of response was 9.1 months. The ORR hit 67% (2 CRs; 2 PRs) among the subgroup of patients with PD-L1–high tumors. Among those with PD-L1–low tumors, the ORR was 17%.

“Simultaneous PD-L1 and PD-1 blockade has been hypothesized to provide synergistic antitumor effects, as inhibitors may have distinct mechanisms of action,” said lead study author Juan Martin-Liberal, MD, PhD, a consultant medical oncologist in the Melanoma, Sarcoma, and Genitourinary Tumors Unit at the Institut Catala d’Oncologia Hospitalet, in Barcelona, Spain, said when presenting the data during the 2020 ESMO Virtual Congress. “[Although] these differences should be taken cautiously given the sample size, these data have provided insights into combining tislelizumab, a clinical stage anti–PD-1 antibody, with anti–PD-L1 antibodies.”

Martin-Liberal shared data from the phase 2B portion of the phase 1/2 BGB-900-101 study. Patients had locally advanced or metastatic urothelial carcinoma that had progressed after at least 1 platinum-containing regimen. Patients had a median age of 69.5 years, and 92% of patients were male. Ten patients had received 1 prior line of systemic therapy. PD-L1–high status was defined as PD-L1 staining on 25% or more of tumor or immune cells with the VENTANA SP263 assay.

Patients received 1350 mg of intravenous (IV) BGB-A333 and 200 mg of IV tislelizumab every 3 weeks. The median treatment duration was 6.2 months and the median follow-up was 10 months.

The disease control rate (DCR) varied based on PD-L1 status. In the overall patient population, the DCR was 75%. In PD-L1–high patients, the DCR was 100% compared with 50% in PD-L1–low patients.

In the overall population, the median progression-free survival (PFS) was 6.1 months. In the PD-L1–high subgroup, the median PFS was 10 months compared with 4.1 months in the PD-L1–low subgroup.

Safety was evaluated in 39 patients, which included patients from phase 1 of the trial. Treatment-related adverse effects (TRAEs) across all grades occurred in 20 patients, with the most common being fatigue (n = 5), maculopapular rash (n = 4), myalgia (n = 4), nausea (n = 4), pruritis (n = 3), asthenia (n = 2), back pain (n = 2), and diarrhea (n = 2). A total of 7 patients experienced a grade 3 or higher TRAE, including 1 report of fatigue and 1 report of maculopapular rash.

Two patients in the phase 2B portion of the study experienced immune-related AEs, which consisted of grade 3 endocrine disorders, grade 3 hypophysitis, grade 2 musculoskeletal and connective tissue disorder, and grade 2 myositis. There were no patient deaths related to study treatment.

1. Martin-Liberal H, Fong P, Moreno V, et al. BGB-A333, an anti-PD-L1 monoclonal antibody, in combination with tislelizumab in patients with urothelial carcinoma. 

Dual immune checkpoint blockade with the PD-1 inhibitor tislelizumab and the PD-L1 inhibitor BGB-A333 showed clinical activity in bladder cancer. 

Dual immunotherapy regimen shows early promise in urothelial carcinoma

A study of molecularly-directed frontline therapy offered insight on the optimal patients to receive various immunotherapy or targeted therapy regimens in the frontline setting for metastatic clear cell renal cell carcinoma (ccRCC).

The noncomparative, phase 2, biomarker-driven BIONIKK trial randomized 4 groups of patients with distinct tumor microenvironment compositions and prior outcomes with sunitinib (Sutent) to nivolumab (Opdivo) monotherapy, nivolumab plus ipilimumab (Yervoy), or a TKI. The subtypes were identified through previous analysis of transcriptomic data from frozen ccRCC specimens.

Groups 1 (ccrcc1) and 4 (ccrcc4) were “immune-low” and “immune-high,” respectively, and were associated with poor outcomes with sunitinib. Conversely, patients in Groups 2 (ccrcc2) and 3 (ccrcc3) had “angio-high” and “normal-like” tumors, respectively, and were associated with favorable outcomes with sunitinib.

Patients in groups 1 and 4 were randomized to receive alone or nivolumab in combination with ipilimumab. Those in groups 2 and 3 were randomized to receive the combination regimen or physician’s choice of TKI with either sunitinib or pazopanib (Votrient).

The study results, which were presented during the 2020 ESMO Virtual Congress, showed that among all evaluable patients in the target cohort (n = 154), the objective response rate (ORR) was 39.3% with nivolumab monotherapy, 44.5% with nivolumab plus ipilimumab, and 50% with a TKI. The ORRs among evaluable patients in an additional cohort (ACE; n = 33) were 41.7%, 54%, and 25%, respectively.

The ORR with nivolumab alone (n = 29) was 20.7% in group 1. The ORR was 39.4% with nivolumab and ipilimumab (n = 33); 6.1% of these were complete responses (CRs), and 33.3% were partial responses (PRs).

In group 4, the ORR was 50.0% with single-agent nivolumab (n = 14) versus 53.0% with the combination of nivolumab and ipilimumab (n = 17). The CR rates were 7.1% and 11.8%, respectively. The PR rates were 42.9% and 41.2%, respectively.

The ORR was 53.8% with a TKI (n = 26) in group 2, compared with 48.3% with the combination regimen (n = 29). Additionally, 13.8% of patients who received the combination derived CRs.

And among patients in group 3 who received a TKI (n = 2), the ORR was 0% compared with 25.0% with nivolumab/ipilimumab (n = 4). No patients on either regimen derived a CR.

“[The] BIONIKK trial provides evidence on the best candidates to receive TKI, nivolumab alone, or nivolumab/ipilimumab,” said lead study author Yann-Alexandre Vano, MD, PhD, a medical oncologist at Hôpital Européen Georges-Pompidou in Paris, France, during a virtual presentation of the data. “We see the highest response rates with nivolumab alone in patients with ccrcc4 tumors, with durable responses.”

“The poor prognosis of these highly infiltrated tumors seems to be reversed by anti–PD-1 treatment,” added Vano. “In patients with ccrcc1 tumors, combination ipilimumab and nivolumab seems to be needed. In patients with ccrcc2 tumors, TKIs provide very high response rates…at 16 months of follow-up.”

To enroll in the trial, patients had to have metastatic RCC with clear cell histology, though patients with translocation carcinoma were allowed to enroll. Additionally, patients had to be previously untreated in the metastatic setting, have an ECOG performance status of 2 or less, and have frozen tumor tissue available for testing.

A quantitative reverse transcription PCR with a 35-gene signature was performed on frozen tissue samples to classify patients into the 4 molecular groups. Following classification, patients were randomized to their respective treatments.

Between June 2017 and July 2019, 15 centers in France screened 308 patients for potential enrollment on the study. In total, 106 patients were excluded from the trial due to not meeting inclusion criteria (n = 43), not having available frozen tissue and/or insufficient quality of specimen (n = 57), declining to participate (n = 4), or patient death during screening (n = 2).

In the target cohort, baseline characteristics were similar between all randomized patients. Common sites of metastases included the lung, lymph node, bone, liver and brain. Additionally, the majority of patients (>50%) had intermediate or poor–risk disease by International Metastatic RCC Database criteria.

At a median follow-up of 16 months, the median progression-free survival (PFS) in Group 1 was 8.0 months with the combination of nivolumab and ipilimumab versus 4.6 months with nivolumab alone. In Group 4, the median PFS was 12.2 months versus 7.8 months, respectively.

The median PFS in group 2 was not reached in the TKI arm compared with 10.4 months with nivolumab plus ipilimumab. In Group 3, the Kaplan-Meier curve was not shown due to the limited number of patients enrolled in the cohort.

At the median follow-up time, 16% of overall survival (OS) events were observed, which translated to immature OS findings.

No statistical tests were performed due to the noncomparative design of the BIONIKK trial.

The median duration of response (DOR) in Group 1 was 6.7 months with nivolumab alone versus 13.9 months with the combination. The median time to response (TTR) was 2.5 months and 2.2 months, respectively. Comparatively, the median DOR in Group 4 was 15.0 months with nivolumab versus 12.3 months with the combination. The median TTR was 2.2 months and 3.5 months, respectively.

The DOR with the combination was 12.0 months in Group 2 versus 20.2 months in Group 3. With a TKI, the DOR was 8.4 months in Group 2; the DOR was not evaluable (NE) in Group 3. The median TTR with the combination was 2.3 months in Group 2 versus 2.2 months in Group 3. With a TKI, the median TTR was 3.1 months and NE, respectively.

“The main findings are that the vast majority of patients responded at the first CT scan,” said Vano, referencing a swimmer plot that was presented with the data. “This is particularly the case for [treatment with] nivolumab [alone] in group 4. In Group 2, around 30% of patients responded very late—after 10 months—which is very uncommon with TKIs.”

Though early, a transcriptomic analysis of immune cells distribution showed that tumors in Group 4 have the highest level of infiltration by immune cells, particularly cytotoxic lymphocytes.

“A huge biomarker program including transcriptomic analyses, 

 protein expression, and analyses of circulating immune cells is currently ongoing,” concluded Vano.

1. Vano Y, Elaidi R, Bennamoun M, et al. Results from the phase 2 BIOmarker driven trial with nivolumab (N) and ipilimumab or VEGFR tyrosine kinase inhibitor (TKI) in naïve metastatic kidney cancer (m-ccRCC) patients (pts): the BIONIKK trial (NCT02960906). Presented at: 2020 ESMO Congress; September 19-21, 2020; Virtual. Abstract: LBA25.

2. Beuselinck B, Job S, Becht E, et al. Molecular subtypes of clear cell renal cell carcinoma are associated with sunitinib response in the metastatic setting. 

. 2015;21(6):1329-1339. doi:10.1158/1078-0432.CCR-14-1128

3. Becht E, Giraldo NA, Beuselinck B, et al. Prognostic and theranostic impact of molecular subtypes and immune classifications in renal cell cancer (RCC) and colorectal cancer (CRC). 

. 2015;4(12):e1049804. doi:10.1080/2162402X.2015.1049804

The results may help guide treatment selection with immunotherapy versus targeted agents in patients with kidney cancer. 

Jessica Hergert

Articles

Novel agent VERU-111 active in pretreated prostate cancer

Dual immunotherapy regimen shows early promise in urothelial carcinoma

Study of molecularly-guided therapy provides precision medicine insight in mRCC