Hayley Virgil

Recently presented cohort 3 results from the phase 2 TROPHY-U-01 trial (NCT03547973) showed a 34% objective response rate (ORR) in patients with checkpoint inhibitor-naïve metastatic urothelial cancer undergoing treatment with second-line sacituzumab govitecan-hziy (Trodelvy) plus pembrolizumab (Keytruda).

The findings were presented at the 2022 Genitourinary Cancers Symposium in San Francisco, California.

At a median follow-up of 5.8 months, patients treated with the combination experienced an ORR of 34% (95% CI, 20.1%-50.6%), and an ORR of 38% among evaluable patients. One patient experienced a complete response (CR), 13 had partial responses (PR), and 11 achieved stable disease. Of those who experienced stable disease, 4 had stable disease for 6 months or more.

“These data support further evaluation of antibody-drug conjugate/checkpoint inhibitor combination [therapy] in metastatic urothelial cancer in the platinum-refractory setting and probably in earlier lines of therapy in a different patient population,” according to lead author Petros Grivas, MD, PhD, a physician at Seattle Cancer Care Alliance; clinical director of the Genitourinary Cancers Program and associate professor of the Division of Medical Oncology at the University of Washington School of Medicine; and associate professor of Clinical Research Division at Fred Hutchinson Cancer Research Center. “Additional follow-up for survival events and biomarkers are ongoing.”

As treatment options for patients with metastatic urothelial cancer remain limited and outcomes poor, investigators aimed to assess other safe and efficacious options to improve patient responses. Investigators theorized that antibody-drug conjugates and checkpoint inhibitors may be a valuable combination strategy capable of providing benefit to patients with metastatic disease.

In cohort 3 of the registrational, open-label multicohort study, investigators enrolled up to 61 patients who were checkpoint inhibitor-naïve with progressive disease following treatment with platinum-based therapies. The cohort received sacituzumab govitecan at a dose of 10 mg/kg on days 1 and 8 every 21 days and 200 mg of pembrolizumab on day 1 every 21 days. Treatment continued until patients experienced unacceptable toxicity or disease progression. Patients needed to be 18 years or older with an ECOG performance status of 0 or 1. Additionally, a creatinine clearance of 30 mL per minute or higher and adequate hepatic function were required.

The study’s primary end point was ORR by investigator review, with key secondary end points including safety, duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

The majority of patients were male (83%) and the median age was 67 years. Most patients were White (54%) and had an ECOG performance status of 1 (61%). In total, 49% and 27% of patients had a Bellmunt risk factor of 1 and 2, respectfully. Investigators also reported 49% of patients underwent neoadjuvant or adjuvant therapy with a median time from end of most recent prior systemic therapy to screening date of 1.6 months. In terms of best response to prior systemic therapy in the metastatic setting, 1 patient had a previous CR and 2 had a PR.

Additional findings from the study indicated that 63% of patients experienced tumor shrinkage and the clinical benefit rate was 61% (95% CI, 44.5%-75.8%). Patients had a median time to response of 2 months and the median DOR was not reached (95% CI, 2.80–not available). The median PFS was 5.5 months (95% CI, 1.7–not reached) and the median OS was not reached.

When examining ORR by subgroup, investigators reported that patients with or without baseline visceral metastases and liver involvement, had rates of 41.7% (95% CI, 15.17%-72.33%) and 31.0% (95% CI, 15.28%-50.83%), respectively. Additionally, for patients who had a Bellmunt risk factor of 0, 1, and 2, the ORRs were 40.0% (95% CI, 12.16%-73.76%), 35.0% (95% CI, 15.39%-59.22%), and 27.3% (95% CI, 6.02%-60.97%).

The most common any grade adverse effects (AEs) in cohort 3 were diarrhea (76%), nausea (59%), and anemia (56%), with grade 3 or higher AEs including neutropenia (27%), diarrhea (24%), anemia (20%), and leukopenia (20%).

The median duration of treatment was 4 months with sacituzumab govitecan and 3.5 months with pembrolizumab. Sixty-eight percent of patients permanently discontinued treatment and 32% were still being treated at the time of data cutoff. Patients who discontinued did so due to progressive disease (51%), withdrawal of consent (5%), and AEs (3%).

Grade 3/4 treatment-related AEs (TRAEs) occurred in 59% of patients, with 39% of patients discontinuing sacituzumab govitecan treatment because of TRAEs. The most common any grade TRAEs were diarrhea (71%), nausea (54%), and neutropenia (44%). Twenty-five percent of patients required a steroid to combat an immune-related AE, with 15% of patients requiring topical and 10% requiring oral steroids for diarrhea (n = 2), pruritis (n = 1), and maculopapular rash (n = 1). Investigators also reported that 29% of patients required granuloma macrophage colony–stimulating factor.

“[Other] TROPHY-U-01 cohorts are being assessed. We have cohort 2 looking at sacituzumab govitecan as a single agent after checkpoint inhibition and cohorts 4 and 5 evaluating sacituzumab govitecan in combination with cisplatin plus or minus avelumab [Bavencio] as induction therapy followed…avelumab [switch maintenance therapy],” Grivas concluded.

1. Grivas P, Poussel D, Park CH, et al. TROPHY-U-01 Cohort 3: sacituzumab govitecan (SG) in combination with pembrolizumab (Pembro) in patients (pts) with metastatic urothelial cancer (mUC) who progressed after platinum (PLT)-based regimens. 

. 2022;40(suppl 6):434. doi:10.1200/JCO.2022.40.6_suppl.434

Articles

“These data support further evaluation of antibody-drug conjugate/checkpoint inhibitor combination [therapy] in metastatic urothelial cancer in the platinum-refractory setting and probably in earlier lines of therapy in a different patient population,” says Petros Grivas, MD, PhD.

Combination sacituzumab govitecan/pembrolizumab shows efficacy and safety in metastatic urothelial cancer

Investigators have launched the phase 2a efficacy analysis portion of a phase 1b/2 trial exploring the combination of the oral immune activator BXCL701 plus the immune checkpoint inhibitor pembrolizumab (Keytruda) in heavily pretreated patients with metastatic castration-resistant prostate cancer (mCRPC) with de novo or treatment-emergent small cell neuroendocrine carcinoma (SCNC).

The decision, which was reported in press release from BXCL701 developer BioXcel Therapeutics, came after the protocol-specified efficacy threshold for cohort expansion of 3 composite responses was met.

 Findings from the phase 1b/2 study (NCT03910660) were presented at the 2021 European Society of Medical Oncology Congress (ESMO) and indicated that those who received treatment with the experimental combination yielded a composite response rate of 26% and a disease control rate of 63%. Moreover, 5% of patients achieved a confirmed partial response (5%) and 11% had an unconfirmed response.

“There is currently no standard of care for [patients with mCRPC] presenting with the SCNC phenotype,” Vincent J. O’Neill, MD, senior vice president and chief medical officer at BioXcel, said in a press release. “SCNC is a particularly rare and difficult to treat variation of mCRPC. The decision to expand the SCNC cohort builds upon positive interim safety and efficacy data from the adenocarcinoma cohort presented last month at ESMO and moves us into the next stage of the evaluation lifecycle.

He continued, “With three composite responses observed among ten evaluable patients, and what we believe is a manageable side effect profile, we continue to be encouraged by BCXL701’s potential to generate an immune response in ‘cold’ tumor types. We intend to continue recruitment of additional patients for our SCNC cohort, and we look forward to the further evaluation of BXCL701 in this mCRPC patient population, as well as in our adenocarcinoma cohort, which also continues enrollment.”

To be eligible for the open-label, multicenter study, patients were required to have experienced progression via Prostate Cancer Working Group 3 criteria, as well as receive at least 1 previous line of treatment with cytotoxic chemotherapy to be enrolled on the SCNC cohort. Moreover, treatment with 1 to 2 androgen signaling inhibitors and 1 line of taxane chemotherapy was necessary to be included in the adenocarcinoma cohort. Investigators reported a total of 23 response-evaluable patients.

Eligible patients who enrolled on the study with SCNC received 0.3 mg of BXCL701 twice daily on days 1 through 14 throughout the 21-day cycle plus 200 mg of intravenous pembrolizumab on day 1 and every subsequent 21-day cycle.

The study’s secondary end points were duration of response, progression-free survival, and overall survival.

Additional findings from the study indicated that 42% of patients achieved stable disease, 5% had a non–complete response or non–progressive disease, and 37% had progressive disease. Moreover, investigators reported a circulating tumor response rate of 25%.

1. BioXcel Therapeutics announces expansion of phase 2 Trial of BXCL701 in de novo and treatment-emergent small-cell neuroendocrine prostate cancer. News release. Published online October 18, 2021. Accessed November 1, 2021. https://bit.ly/3G8BR3s.

2. Monk P, Zhang J, Costin D, et al. BXCL701 - 1st-in-class oral activator of systemic innate immunity-combined with pembrolizumab, in men with metastatic castration-resistant prostate cancer (mCRPC): Phase II results. 

. 2021;32(suppl 5):S626-S677. doi:10.1016/j.annonc.2021.08.1123

A phase 2a efficacy analysis has been launched exploring the combination of the novel oral immune activator BXCL701 and pembrolizumab in prostate cancer patients with de novo or treatment-emergent small cell neuroendocrine carcinoma.

Oral immune activator BXCL701 advances in pipeline for neuroendocrine prostate cancer

An analysis across 5 clinical trials in advanced renal cell carcinoma (RCC) showed a survival benefit with frontline immunotherapy versus sunitinib (Sutent) in the total patient population; however, when stratifying patients by risk status, it remained inconclusive whether upfront immunotherapy was optimal in patients with favorable-risk disease.

Investigators reported at the 2021 ESMO Congress that all clinical trials included in the analysis reported an advantage to overall survival (OS) and progression-free survival (PFS) with an immunotherapy regimen compared with sunitinib (HR for OS, 0.71; 95% CI, 0.61-0.84; HR for PFS, 0.64; 95% CI, 0.51-0.82). Notably, the favorable-risk subgroup analysis indicated that no difference was observed in terms of OS between the treatment cohorts (HR, 1.07; 95% CI, 0.81-1.41) with a trend toward an advantage of immunotherapy for PFS (HR, 0.74; 95% CI, 0.46-1.19).

Due to recent evidence indicating that this patient population may experience an improved prognosis after being treated with immunotherapy, investigators launched the meta-analysis to evaluate the safety and efficacy of first-line immunotherapy compared with sunitinib in those with favorable-risk advanced RCC.

Investigators underwent a systemic search of PubMed, Ovid MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials, and the evidence was assessed for quality. Survival hazard ratios were extracted for both the overall patient population and the favorable-risk subgroup.

Investigators used findings from 5 clinical trials, including the phase 3 CheckMate 9ER trial (NCT03141177), which examined nivolumab (Opdivo) plus cabozantinib (Cabometyx) versus sunitinib in previously untreated RCC; the phase 3 CheckMate214 trial (NCT02231749) which examined nivolumab plus ipilimumab (Yervoy); the phase 3 JAVELIN Renal 101 study (NCT02684006), which examined avelumab (Bavencio) plus axitinib (Inlyta); the phase 3 KEYNOTE-426 study (NCT02853331), which examined pembrolizumab (Keytruda) plus axitinib; and the phase 3 CLEAR trial (NCT02811861), which examined lenvatinib (Lenvima) plus pembrolizumab. The meta-analysis included a total of 1088 patients.

For the favorable-risk population in the CheckMate 9ER trial, investigators reported a hazard ratio (HR) of 0.84 for OS (95% CI, 0.35-1.97) and an HR of 0.62 (95% CI, 0.38-1.01) for PFS. Additionally, in the CheckMate214 trial, investigators reported HRs of 1.19 (95% CI, 0.77-1.85) and 1.65 (95% CI, 1.16-2.35) for OS and PFS, respectively, within the same patient population. The JAVELIN Renal 101 trial reported an HR of 0.81 (95% CI, 0.34-1.96) for OS and 0.63 for PFS (95% CI, 0.40-0.99) in the favorable-risk population. Moreover, the KEYNOTE-426 study reported HRs of 1.06 (95% CI, 0.60-1.86) and 0.79 (95% CI, 0.57-1.09) for OS and PFS, respectively. Lastly, the CLEAR trial reported HRs of 1.15 (95% CI, 0.55-2.40) and 0.41 (95% CI, 0.28-0.62) for OS and PFS, respectively, in this patient population.

Moreover, investigators noted that the safety profile appeared to be consistent with previously reported findings.

As the survival advantage garnered from an immunotherapy regimen has not yet been confirmed among those with favorable-risk advanced RCC, additional prospective trials containing a larger sample size and longer follow up are needed in order to confirm the benefit.

1. Manneh R, Lema M, Ibatá L, et al. Immunotherapy vs sunitinib as first-line treatment for advanced renal cell carcinoma in favourable risk patients. A meta-analysis of randomized clinical trials. Poster presented at 2021 European Society of Medical Oncology Annual Congress; September 16-21, 2021; virtual. Accessed September 16, 2021. Abstract 677P.

Additional prospective trials containing a larger sample size and longer follow up are needed to determine the optimal treatment sequence in favorable-risk advanced renal cell carcinoma. 

Frontline immunotherapy benefit in favorable-risk advanced RCC remains inconclusive

The FDA has officially released its finalized recommendation for the use of metastases-free survival (MFS) as an end point in clinical trials evaluating treatments for patients with nonmetastatic castration-resistant prostate cancer (nmCRPC).

In addition to including editorial changes for clarity, the guidance also has recommendations for sponsors on aspects such as general trial design, imaging, and considerations for interpreting data from the trial and MFS analyses.

A prolonged assessment period and low death rate means that the utility of overall survival (OS) can be impractical as a primary end point to support drug approvals for patients with prostate cancer. These issues were explored during the 2011 Oncologic Drugs Advisory Committee meeting wherein members recommended that other end points be explored that can be measured earlier in the disease course, such as MFS which could prove to be useful in evaluating the impact of treatment in this patient population.

The guidance highlighted several general considerations for clinical trial designs that utilize MFS as an end point. For example, the FDA recommends defining MFS prior to starting the trial—which should exclude local progression events such as progression in pelvic lymph nodes below the aortic bifurcation—as well as considering stratification of randomization by prior local definitive therapy or lack of prior definitive therapy. Prostate-specific antigen (PSA) doubling time should also be considered, according to the guidance.

Other recommendations include utilizing a superiority trial design and excluding patients who are likely to benefit from local therapy. This population of patients could be enrolled following local therapy provided that their PSA continues to rise and other enrollment criteria for CRPC and minimum PSA value are met.

In terms of imaging consideration, the guidance states that sponsors ought to prespecify acceptable imaging modalities and how often assessments should be completed. Additionally, it is important to prespecify and justify the radiographic definition of nonmetastatic disease. Radiographic definition of local disease and progression, as well as metastatic disease, should also be prespecified. In order to interpreted results with MFS, the significance of MFS improvement should be notably greater than frequency of imaging.

“FDA recommends a blinded independent central review of imaging studies to assess any potential assessment bias. Sponsors may also consider using an audit where a random sample of scans are sent for independent review. Sponsors should seek advice from the Agency about the design of an audit for MFS,” the guidance stated.

When it comes to interpreting the results of trials utilizing MFS as an end point, interim efficacy analyses of MFS are discouraged to avoid over overestimating and underestimating MFS benefit. Moreover, the magnitude of MFS improvement that is required to support drug approval will be based on trial design, safety, patient population, and overall risk/benefit assessment. Additionally, although demonstration of OS benefit is not required, a formal interim OS analysis should be conducted at the time of final MFS analysis.

Lastly, the guidance highlighted several final considerations for MFS analyses. As missing data may complicate MFS analyses, it is imperative to put procedures in place that minimize missing data.

“The statistical analysis plan should specify the primary analysis and one or more sensitivity analyses to evaluate the effect of missing observations on the results,” the guidance read. “Sponsors can consider additional analyses of progression-free survival (including both local and metastatic progression) to support the primary MFS analysis.”

Before the draft guidance was released, the FDA had approved the use of apalutamide (Erleada) in February 2018 for patients with nmCRPC, marking it as the first drug approved on the basis of a clinical trial with an MFS primary end point.

 The phase 3 SPARTAN trial (NCT01946204) enrolled 1207 patients with nmCRPC who were treated with either apalutamide or placebo. Results indicated that apalutamide yielded a median MFS of 40.5 months vs 16.2 months in those who received placebo (HR, 0.28; 95% CI, 0.23-0.35; 

Similarly, enzalutamide (Xtandi) received approval in July 2018 for the treatment of nmCRPC with MFS, which was defined as the time from randomization to loco-regional and/or distant radiographic progression or death up to 112 days following treatment discontinuation with no radiographic progression, as the primary end point of the supporting trial.

 Findings from the supporting phase 3 PROSPER trial (NCT020032924) indicated that enzalutamide yielded a median MFS of 36.6 months vs 14.7 months in the control arm (HR, 0.29; 95% CI, 95% CI, 0.24-0.35; 

Lastly, the FDA approval of darolutamide (Nubeqa) on July 30, 2019, was based on the results of the phase 3 ARAMIS (NCT02200614) trial, in which 1509 patients with nmCRPC achieved a significant improvement in MFS, the primary end point of the study.

 For this trial, MFS was defined as the time from randomization to first signs of distant metastases or death from any cause within 33 weeks of the patient’s last evaluable scan. Those who received the experimental agent experienced a median MFS of 40.4 months vs 18.4 months among those in the placebo arm (HR, 0.41; 95% CI, 0.34-.050; 

 <.0001). Notably, the OS data were not mature.

FDA. Nonmetastatic Castration-Resistant Prostate Cancer: Considerations for Metastasis-Free Survival Endpoint in Clinical Trials, version 8.21. Accessed August 9, 2021. https://bit.ly/3s0o4FG

FDA approves new treatment for a certain type of prostate cancer using novel clinical trial endpoint. News release. FDA. February 14, 2018. Accessed August 6, 2021. 

Smith MR, Saad F, Chowdhury S, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. 

. 2018;378(15):1408-1418. doi:10.1056/NEJMoa1715546

FDA approves enzalutamide for castration-resistant prostate cancer. News release. July 13, 2018. Accessed August 9, 2021. 

Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer

. 2018;378:2465-2474. doi:10.1056/NEJMoa1800536

FDA approves darolutamide for non-metastatic castration-resistant prostate cancer. News release. FDA. July 30, 2019. Accessed August 9, 2021. 

Fizazi K, Shore N, Tammela TL, et al. Darolutamide in nonmetastatic, castration-resistant prostate cancer. 

. 2019;380:1235-1246. doi:10.1056/NEJMoa1815671

The FDA has officially released its finalized recommendation for the use of metastases-free survival as an end point in clinical trials evaluating treatments for patients with nonmetastatic castration-resistant prostate cancer.

Hayley Virgil

Articles

Combination sacituzumab govitecan/pembrolizumab shows efficacy and safety in metastatic urothelial cancer

Oral immune activator BXCL701 advances in pipeline for neuroendocrine prostate cancer

Frontline immunotherapy benefit in favorable-risk advanced RCC remains inconclusive

Final FDA blueprint available for MFS end point in nonmetastatic CRPC trials