Lisa Astor 

Updated phase 2 data presented at the 2021 ASCO Annual Meeting showed that the HIF-2α inhibitor belzutifan (MK-6482) continued to induce strong responses as a first-line treatment for patients with Von-Hippel Lindau (VHL)–associated renal cell carcinoma (RCC).

The investigational agent also showed activity against other VHL-associated neoplasms, according to lead study author Ramaprasad Srinivasan, MD, PhD, and coinvestigators.

“This update continues to demonstrate the activity of belzutifan in patients with VHL-associated renal and non-renal tumors accompanied by an acceptable safety profile,” said Srinivasan, head of the Molecular Cancer Therapeutics Section, Center for Cancer Research, National Cancer Institute.

Recently, the FDA granted belzutifan a priority review for the treatment of patients with VHL disease–associated RCC who do not require immediate surgery based on earlier results of this study.2

The open-label, single-arm study enrolled 61 patients who were diagnosed with VHL disease based on germline alteration who had at least 1 measurable RCC tumor, had not received any prior systemic anticancer therapy, did not have metastatic disease, and had an ECOG performance status of 0 or 1. Patients were treated with 120 mg oral daily belzutifan as a potential systemic treatment for VHL-associated RCC and other VHL neoplasms.

Objective response rate (ORR) in RCC tumors per RECIST criteria by independent review committee was the primary end point and secondary end points included ORR in non-RCC neoplasms, duration of response (DOR), and safety.

The median age was 41 years (range, 19-66) at baseline and the majority of patients were male (52.5%) and had an ECOG performance status of 0 (82.0%). Pancreatic lesions were also reported in all patients, 36.1% of which were neuroendocrine; central nervous system (CNS) hemangioblastomas were reported in 82.0% of patients and retinal lesions in 26.2%.

As of data cutoff, a median of 21.8 months (range, 20.2-30.1) after enrollment, 88.5% of patients were still receiving treatment.

Responses in target RCC lesions were observed in 30 patients (49.2%; 95% CI, 36.1%-62.3%) of patients by independent review committee; all responses were partial responses (PRs), and another 4 patients had unconfirmed PRs. Stable disease was reported in 49.2% of patients and 1 patient was not evaluable. Ninety-two percent of patients had a decrease in target RCC lesion size.

The median time to response was 8.2 months (range, 2.7-19.1) and the duration of response was not reached (range, 2.8+ to 22.3+). Progression-free survival rate at 12 months was 98.3% and 96.5% at 24 months, and the median has not yet been reached.

In pancreatic lesions, responses were reported in 77.0% (95% CI, 64.5%-86.8%), with complete responses (CRs) in 9.8% and PRs in 67.2%. Among pancreatic neuroendocrine tumors, the ORR was 90.9% (95% CI, 70.8%-98.9%) with CRs in 13.6% and PRs in 77.3%. The ORR was 30.0% (95% CI, 17.9%-44.6%) in CNS hemangioblastomas with CRs in 6.0% and PRs in 24.0%.

Srinivasan noted that retinal hemangioblastomas were not amenable to classic response evaluation with RECIST criteria. Sixty-nine percent of retinal hemangioblastomas were improved and 31% were stable as best response.

All patients reported a treatment-related adverse event (TRAE) of any grade, grade 3 events were observed in 32.8% and grade 4 or 5 events in 14.8%. TRAEs led to discontinuation in 1.6% of patients and an adverse event led to death in 1 patient, but the event was not treatment related.

The most common AEs of any grade were anemia (90.2%), fatigue (65.6%), headache (41.0%), dizziness (39.3%), and nausea (34.4%). Most of the events were grade 1 or 2, but common grade 3 events were anemia (8.2%) and hypertension (8.2%). Srinivasan said that anemia was a predicted on-target effect of HIF-2–dependent downregulation of erythropoietin.

1. Srinivasan R, Donskov F, Iliopoulos O, et al. Phase 2 study of belzutifan (MK-6482), an oral hypoxia-inducible factor 2α (HIF-2α) inhibitor, for Von Hippel-Lindau (VHL) disease-associated clear cell renal cell carcinoma (ccRCC). 

2021;39(suppl 15):4555. doi:10.1200/JCO.2021.39.15_suppl.4555

2. Merck Receives Priority Review from FDA for New Drug Application for HIF-2α Inhibitor Belzutifan (MK-6482). News release. Merck. March 16, 2021. Accessed June 7, 2021. https://bit.ly/38NLYM2

Articles

The HIF-2α inhibitor continued to induce strong responses in patients with Von-Hippel Lindau (VHL)–associated renal cell carcinoma and other VHL-associated neoplasms.

Update sustains strong activity with belzutifan in VHL-associated kidney cancer

Results from the confirmatory phase 3 EV-301 trial shared during the 2021 Genitourinary (GU) Cancers Symposium showed that the antibody-drug conjugate enfortumab vedotin (Padcev) reduced the risk of death by 30% versus chemotherapy in patients with heavily pretreated locally advanced or metastatic urothelial carcinoma.

Patients enrolled in the trial had previously received platinum-based chemotherapy and a PD-1/L1 inhibitor. The findings, which were simultaneously published in the 

, showed that enfortumab vedotin improved overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) versus chemotherapy in this patient population.

“Enfortumab vedotin is the first drug beyond chemotherapy and immunotherapy to show a significant survival advantage in previously treated advanced urothelial cancer,” said Thomas Powles, MBBS, MRCP, MD, in a presentation during the GU Cancers Symposium. “This is a big step in the right direction for patients with advanced urothelial cancer, where treatment options remain quite limited.”

The Nectin-4–directed antibody-drug conjugate was granted an accelerated approval by the FDA in December 2019 for the treatment of adult patients with locally advanced or urothelial cancer who have previously received a PD-1/ L1 inhibitor and platinum-containing chemotherapy.

 Accelerated approval was granted because treatment options are limited once urothelial cancer has progressed on both chemotherapy and immunotherapy. Data from the phase 2 EV-201 trial supported the approval.

The open-label, randomized EV-301 trial (NCT03474107) served as a confirmatory trial for the benefit of enfortumab vedotin over chemotherapy in this setting following the FDA approval.

A total of 608 patients with histologically or cytologically confirmed urothelial cancer, including patients with squamous differentiation or mixed cell types, were enrolled in the study and randomized 1:1 with stratification to either the enfortumab vedotin (n = 301) arm or the chemotherapy arm (n = 307). Eligible patients had radiographic progression or relapsed during or after immune checkpoint inhibition for the treatment of advanced urothelial cancer and had received prior platinum-containing chemotherapy; patients also had an ECOG performance status of 0 or 1. Stratification variables included ECOG performance status (0 or 1), region of the world, and the presence or absence of liver metastasis.

In the investigational arm, enfortumab vedotin was administered at 1.25 mg/kg on days 1, 8, and 15 of every 28-day cycle. Chemotherapy in the control arm consisted of docetaxel at 75 mg/m2, paclitaxel at 175 mg/m2, or vinflunine 320 mg/m2 each given on day 1 of every 21-day cycle.

OS was the primary end point of the study and secondary end points included PFS, ORR, disease control rate (DCR)—all assessed by the investigator per RECIST v1.1 criteria—and safety.

With enrollment of approximately 600 patients, the study had 85% power to detect a statistically significant difference in efficacy at an overall 1-sided 0.025 type I error rate with a hazard ratio of 0.75.

The trial was planned to have 2 analyses, an interim one at 285 deaths (65%) and a final analysis at 439. For the interim analysis, OS was tested with a 1-sided difference of 0.00679.

Powles, a professor of genitourinary oncology, director of the Barts Cancer Center, and lead for Solid Tumor Research at the Barts Cancer Institute, in London, United Kingdom, explained that as interim analysis was positive for survival this became the primary analysis.

Baseline characteristics were balanced between the 2 arms. The median age was 68 years and more than three-fourths of patients were male. Only 14% of patients were from the United States, 60% had an ECOG performance status of 1, two-thirds had a Bellmunt risk score of 0 or 1, 31% had liver metastases, and 87% had 1 or 2 prior lines of therapy. In the enfortumab vedotin arm, 20% responded to prior immune checkpoint inhibition and 16% responded in the chemotherapy arm.

As of data cutoff, 81% of patients had discontinued treatment in the enfortumab vedotin arm versus 93% in the chemotherapy arm, which was due to progressive disease in 59% of patients in both arms. At a median follow-up of 11.1 months, the median treatment exposure was 5.0 months (range, 0.5-19.4) in the enfortumab vedotin and 3.5 months (range, 0.2-15.0) in the chemotherapy arm.

The median OS with enfortumab vedotin was 12.88 months (95% CI, 10.58-15.21) versus 8.97 months (95% CI, 8.05-10.74) with chemotherapy, which translated to a 30% reduction in the risk of death (HR, 0.70; 95% CI, 0.56-0.89; 

= .00142). Powles commented that the Kaplain-Meier curves for OS “go apart and stay apart, and the data look impressive in my opinion.”

Subgroup analyses for OS favored the enfortumab vedotin arm for all groups excepts female patients (HR, 1.17), although Powles noted that some of the subgroups were too small to draw conclusions.

Median PFS with enfortumab vedotin was 5.55 months (95% CI, 5.32-5.82) versus 3.71 months (95% CI, 3.52-3.94) with chemotherapy (HR, 0.62; 95% CI, 0.51-0.75; 

Confirmed ORR in the enfortumab vedotin arm was 40.6% (95% CI, 34.9%-46.5%), which included complete responses in 4.9%, and the DCR was 71.9% (95% CI, 66.3%-77.0%). In the chemotherapy arm, the ORR was 17.9% (95% CI, 13.7%-22.8%) with complete responses in 2.7%, and a DCR of 53.4% (95% CI, 47.5%-59.2%; 

Treatment-related adverse event (TRAE) rates were similar between the 2 arms, with any-TRAE rates of 94% in the investigational arm and 92% in the control arm, and grade ≥3 TRAE rates of 51% and 50%, respectively. Serious TRAEs were reported in 23% of patients in each arm and TRAEs led to treatment discontinuation in 14% of patients in the enfortumab vedotin arm and 11% in the chemotherapy arm.

Powles highlighted that the rate of grade ≥3 maculopapular rash was increased in the enfortumab vedotin arm (7% vs 0%), whereas rates of grade ≥3 neutrophil count decrease (6% vs 13%), white blood cell count decrease (1% vs 7%), and febrile neutropenia (1% vs 6%) were all higher in the chemotherapy arm.

TRAEs of special interest in the enfortumab vedotin arm included skin reactions of rash (all grade, 44%; grade ≥3, 15%) and severe cutaneous adverse reactions (all grade, 20%; grade ≥3, 5%), peripheral neuropathy in terms of sensory events (all grade, 44%; grade ≥3, 4%) and motor events (all grade, 7%; grade ≥3, 2%), and hyperglycemia (all grade, 6%; grade ≥3, 4%). The majority of TRAEs of special interest were mild to moderate in severity.

1. Powles T, Rosenberg JE, Sonpavde G, et al. Primary results of EV-301: A phase III trial of enfortumab vedotin versus chemotherapy in patients with previously treated locally advanced or metastatic urothelial carcinoma. 

2021;39(suppl 6):393. doi:10.1200/JCO.2021.39.6_suppl.393

2. Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. Published online February 12, 2021. 

3. FDA approves new type of therapy to treat advanced urothelial cancer. FDA website. December 18, 2019. Accessed February 12, 2021. https://bit.ly/3agPr77

The antibody-drug conjugate was previously granted an accelerated approval by the FDA in this setting based on results from the phase 2 EV-201 trial.

Enfortumab Vedotin extends overall survival in phase 3 confirmatory urothelial carcinoma trial

Safety and tolerability results from a phase 1 study of neoadjuvant nivolumab (Opdivo) in patients with nonmetastatic high-risk clear cell renal cell carcinoma (ccRCC) support further research with the anti–PD-1 immune checkpoint inhibitor in this setting.

On a phase 1 study poster shared during the 2020 Society of Urologic Oncology Annual Meeting, first author Hiten D. Patel, MD, MPH, of the Department of Urology at Loyola University Medical Center, and coauthors wrote, “[this] early phase trial demonstrates the safety of neoadjuvant PD-1 blockade with preserved [quality of life] when administered to patients with nonmetastatic high risk ccRCC.”

Immune checkpoint inhibitors have demonstrated significant efficacy in treating patients with treatment-naïve metastatic RCC compared with the prior standard-of-care sunitinib (Sutent), as with the FDA-approved combination of nivolumab and ipilimumab (Yervoy).

 The investigators sought to discover if the benefit of PD-1/PD-L1 inhibitors could be extended to the neoadjuvant setting, as an earlier study of neoadjuvant treatment with the multikinase inhibitor axitinib (Inlyta) had demonstrated significant shrinking of RCC tumors prior to surgery.

The study was a prospective, open-label, single arm phase 1 trial (NCT02575222) that explored the safety and tolerability of nivolumab prior to surgery in patients with resectable nonmetastatic high-risk RCC. Patients with T2a-T4 with or without positive lymph nodes were eligible for the study if they were scheduled to undergo a partial or radical nephrectomy, had an ECOG performance status of 0 or 1, and adequate organ and bone marrow function.

Safety was the primary end point by CTCAE version 4.0 and secondary end points included objective tumor response rate by both RECIST and immune-related RECIST criteria, quality of life, metastasis-free survival, and overall survival.

Nivolumab was administered at 3 mg/kg on day 1 of each of a total of 3 consecutive 14-day cycles. Treatment was followed by surgery within 7 days of completion of the third cycle.

A total of 17 patients were included in the early-phase trial consisting of 16 with ccRCC and 1 with papillary disease. Fifteen had stage cT3a disease, 2 had cT3b, and all were negative for lymph node involvement.

Grade 3 adverse events (AEs) were reported in 11.8% of patients, and no grade 4 or 5 events were reported. AEs of any grade were reported in 82.4% of patients and were considered potentially due to nivolumab in 58.8%. The most common AEs reported were fatigue (41.2%), pruritis (29.4%), and rash (29.4%), all grade 1 in severity.

No delays were reported in surgery, and no postoperative complications of Clavien grade 3 or higher were observed.

At 24.7 months of median follow-up, the 2-year metastasis-free survival rate was 85.1%, and the overall survival rate was 100%.

The 15 patients with ccRCC were restaged prior to surgery, but an overall minimal difference was observed in both the long and short axes from baseline to after treatment with nivolumab. However, 1 patient had an immune-related pathologic response and the rest had stable disease by radiographic criteria.

The 1 patient who achieved a pathologic response demonstrated a regression bed with features of wound healing as well as immune infiltration.

“Data suggest a proportion of patients may experience an immunologic response to treatment despite small impact on tumor volume with a short course of therapy,” Hiten et al wrote.

Patients also reported in the Functional Assessment of Cancer Therapy-Kidney Symptom Index questionnaire an improvement in quality-of-life measurements, especially at 12 months after surgery.

Neoadjuvant nivolumab is also currently being studied in the phase 3 PROSPER RCC study in comparison with observation for patients with RCC undergoing nephrectomy (NCT03055013).

1. Patel HD, Gorin MA, Rowe SP, et al. Neoadjuvant nivolumab in patients with high-risk non-metastatic renal cell carcinoma. Presented at: 2020 SUO Annual Meeting; December 2-5, 2020; Virtual. Abstract 92.

2. Motzer RJ, Tannir NM, McDermott DF, et al; CheckMate 214 Investigators. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. 

. 2018;378:1277-1290. doi:10.1056/NEJMoa1712126

3. Karam JA, Devine CE, Urbauer DL, et al. Phase 2 trial of neoadjuvant axitinib in patients with locally advanced nonmetastatic clear cell renal cell carcinoma. 

2014;66(5):874-880. doi:10.1016/j.eururo.2014.01.035

Phase 1 data suggest the anti–PD-1 immune checkpoint inhibitor is safe and tolerable in the neoadjuvant setting for patients with nonmetastatic high-risk clear cell renal cell carcinoma.

Lisa Astor

Articles

Update sustains strong activity with belzutifan in VHL-associated kidney cancer

Enfortumab Vedotin extends overall survival in phase 3 confirmatory urothelial carcinoma trial

Safety data support continued exploration of neoadjuvant nivolumab in RCC