February 2021 Edition Vol.13, Issue 2

2021 GU: CLEAR, CheckMate 274 and EV-301 Trials Offer Potential to Expand Treatment

By Jennifer Lubell

The American Society of Clinical Oncology’s 2021 Genitourinary (GU) Cancers Symposium sought to combine translational science and practice-changing research in its virtual format, offering the latest data on new therapy combinations for advanced kidney cancer patients while taking a second look at surgery to improve long-term quality of life in testicular cancer.

GU cancer is on a fast track with clinical research, according to Stephen A. Boorjian, MD, a urologist and the Carl Rosen Professor of Urology at Mayo Clinic in Rochester, Minnesota, who served as the Program Committee Chair for the conference. The aim of the GU Cancers Symposium agenda “was to provide a bench to bedside learning experience, highlighting breakthroughs in cancer developments that have every day clinical applications,” he said.

Presentations underscored the critical nature of interdisciplinary care in managing patients and doing both clinical and translational research in urologic cancers, said Robert Dreicer, MD, deputy director of the University of Virginia Cancer Center. “We had an outstanding display of this in all the disease sessions with urologists, radiation and medical oncologists demonstrating how the field is moving forward,” he said.

The fact that important papers were released and presented even as the COVID-19 pandemic continues to disrupt medical research, “underscores the high quality of research and emphasizes the passion of our field for improving future patient outcomes,” Dr. Boorjian said.

First-Line Treatment for RCC

One of those late-breaking papers is the CLEAR trial (Abstract 269), which compared lenvatinib plus pembrolizumab and lenvatinib plus everolimus to sunitinib as first-line treatments for patients with advanced renal cell carcinoma (RCC). The study’s findings, which were presented by Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center in New York, were simultaneously published in the New England Journal of Medicine.

“In kidney cancer, we’re constantly aiming to move the needle forward,” Dr. Boorjian said. The CLEAR trial findings offer an opportunity to potentially expand options with advanced kidney cancer. “It was an honor to have this paper at the meeting.”

Investigators randomized 1,069 patients with advanced clear cell RCC and no prior systemic therapy in a 1:1:1 fashion to receive lenvatinib 20 mg orally once daily plus pembrolizumab 200 mg IV every three weeks; lenvatinib 18 mg plus everolimus 5 mg orally once daily; or sunitinib 50 mg orally once daily (four weeks on and two weeks off).

Both lenvatinib combination arms met the primary endpoint by showing a benefit in PFS, compared with sunitinib alone. Dr. Dreicer said he was impressed with the lenvatinib/pembrolizumab results, which “demonstrated significant improvement in progression-free and overall survival, and objective response rates,” he said.

Lenvatinib plus pembrolizumab significantly improved median PFS over sunitinib alone, at 23.9 months versus 9.2 months (Hazard Ratio [HR] 0.39; 95% CI: 0.32–0.49; P < 0.001). The lenvatinib plus pembrolizumab regimen also significantly improved overall survival, compared with sunitinib (HR 0.66; 95% CI: 0.49-0.88; P= 0.005).

If approved by U.S. FDA, this combination would provide another option for patients with metastatic renal cancer, Dr. Dreicer said.

Dr. Aragon-Ching discusses the design and outcomes of the CHECKMATE -274 trial and some of the questions the data poses:

Breakthroughs on Bladder Cancer

Several presentations described promising therapy combinations for urothelial carcinoma. Findings from the CheckMate 274 trial (Abstract 391) were especially noteworthy, Dr. Boorjian said. “With advanced bladder cancer, we really have a lack of consensus on the benefit of adjuvant therapy after surgical resection,” he said.

The CheckMate 274 study provides first results in adjuvant nivolumab versus placebo in patients who underwent radical surgery for high-risk muscle-invasive urothelial carcinoma.

Nivolumab is a programmed cell death protein (PD-1) immune checkpoint inhibitor approved as a monotherapy to treat platinum-resistant metastatic urothelial cancer. To date, no immune checkpoint inhibitor had shown success as an adjuvant therapy in these patients, according to Dean F. Bajorin, MD, a medical oncologist with Memorial Sloan Kettering Cancer Center in New York, who presented the findings.

Investigators randomized 709 patients to either nivolumab or placebo. Primary endpoints included disease-free survival (DFS) in the intention to treat population and DFS in all randomized patients with tumor PD-L1 (ligand 1) expression ≥ 1%.

The trial met these primary endpoints. “In the [intention to treat] population, the hazard ratio was 0.70, corresponding to a 30% reduction in the risk of disease recurrence or death with nivolumab,” Dr. Bajorin said in his presentation. The drug nearly doubled median disease-free survival, compared with placebo. In the PD-L1 population, the hazard ratio was 0.53, “corresponding to a 47% reduction in the risk of disease recurrence with nivolumab,” he said.

The results showed a statistically and clinically meaningful improvement in DFS in a placebo-controlled trial of a highly lethal disease, Dr. Dreicer said. “If the label for nivolumab is broadened by the FDA, this therapy will become an important addition to our management approach to high-risk bladder cancer patients after radical cystectomy.”

Primary results from the EV-301 study (Abstract 393), a phase 3 trial of enfortumab vedotin versus chemotherapy in patients with previously treated locally advanced or metastatic urothelial carcinoma, also has important implications for clinical practice.

“Enfortumab vedotin is a very active agent, now being broadly studied in a variety of settings in combination with pembrolizumab,” Dr. Dreicer said.

The study demonstrated that this antibody-drug conjugate improved overall survival in patients with advanced urothelial cancer who were previously treated with platinum-based chemotherapy and a PD-1/L1 inhibitor, compared with second-line chemotherapy.

Investigators randomized 608 patients in a 1:1 fashion to receive EV or pre-selected chemotherapy. The EV group had a median overall survival of 12.9 months, compared with 8.97 months in the chemotherapy group (HR 0.70; 95% CI: 0.56-0.89, P=0.001).

EV also significantly improved PFS (5.6 months) versus chemotherapy (3.7 months), as well as overall response rate (40.6% versus 17.9%) and disease control rate (71.9% versus 53.4%). Subgroup analyses showed a benefit with EV, which demonstrated a tolerable and manageable safety profile.

EV is the first drug to show a significant survival advantage beyond chemotherapy and immunotherapy in these patients, according to Thomas Powles, MD, PhD, director of Barts Cancer Centre, Queen Mary University of London, who presented the study findings.

Dr. Powles summarizes the findings from the EV-301 study:

Long-Term Treatment Toxicity

A phase 2 trial in testicular cancer offers the potential for younger patients to avoid long-term toxicities that occur with standard treatments. The Surgery in Early Metastatic Seminoma (SEMS) trial (Abstract 375) established retroperitoneal lymph node dissection (RPLND) as a first-line treatment in early metastatic seminoma, according to Dr. Boorjian, who was a co-investigator of the study.

Surgical trials are somewhat unusual, yet this one addressed a disease space that has had little progress in 30 years, he said. Testicular cancer patients with isolated retroperitoneal disease are usually treated with either radiation or chemotherapy. While the cure rates with these treatments are high, many of the patients are younger and face years of potential cumulative toxicities, including cardiac events, secondary cancers, infertility, neurotoxicity, and metabolic syndrome.

The investigators asked, “Is there a treatment that can reduce long-term morbidity?” said presenter Siamak Daneshmand, MD, an associate professor of urology with Keck Medicine of the University of Southern California. RPLND had shown previous success in treating non-seminomatous germ cell tumors. Dr. Daneshmand and colleagues explored this method as a first-line treatment in 55 patients with pure, early-stage testicular seminoma over a 4-year period. The mean age of the patients in the trial was 34 years and most were White/Caucasian.

The trial’s 2-year recurrence free survival rate was 84%, and the overall recurrence rate was 18%, with a median time to recurrence of about 8 months. With 2-year median follow-up, the overall survival was 100%.

Just 13% of patients had short-term complications, most of which were minor, and none experienced long-term complications, Dr. Daneshmand reported.

The trial data establishes RPLND as a viable treatment alternative, concluded Dr. Daneshmand. “I think it’s an attractive option given favorable long-term morbidity of RPLND,” he said.

Update: Co-developers Seagen and Astellas announced the submission of two supplemental Biologics License Applications (sBLAs) to the FDA for Padcev® (enfortumab vedotin-ejfv) in locally advanced or metastatic urothelial cancer on February 18, 2021.  (See here for more information: https://investor.seagen.com/press-releases/news-details/2021/Seagen-and-Astellas-Announce-Submission-of-Two-Supplemental-Biologics-License-Applications-to-the-U.S.-FDA-for-PADCEV-enfortumab-vedotin-ejfv-in-Locally-Advanced-or-Metastatic-Urothelial-Cancer/default.aspx.)


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