A combination of Keytruda (pembrolizumab) and Lenvima (lenvatinib) worked better than standard Sutent (sunitinib) at delaying disease progression and prolonging survival in adults with untreated advanced renal cell carcinoma (RCC) — the most common type of kidney cancer in adults — according to data from a Phase 3 clinical trial.
In addition, Lenvima also outperformed Sutent in this patient population when combined with Afinitor (everolimus) — an approved second-line therapy for advanced RCC — but to a lesser extent than in combination with Keytruda.
“In this trial, Keytruda plus Lenvima demonstrated superior efficacy benefits compared with [Sutent],” Gregory Lubiniecki, MD, vice president of Merck Research Laboratories’ oncology clinical research, said in a press release. Known as MSD outside North America, Merck is the developer of Keytruda, which has been approved by the U.S. Food and Drug Administration and the European Commission for the treatment of a range of advanced cancers.
Merck and Eisai, Lenvima’s developer, plan to submit applications to regulatory agencies seeking the approval of the Keytruda-Lenvima combo as a first-line treatment for advanced RCC.
“If approved, we believe this combination has the potential to be an important new treatment option for patients with advanced renal cell carcinoma in the first-line setting,” Lubiniecki said.
The study’s findings were presented at the 2021 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, recently held virtually, and simultaneously published in The New England Journal of Medicine.
An immune-checkpoint inhibitor, Keytruda works by stopping a mechanism often used by cancer cells to evade immune system attacks, thereby boosting anti-cancer responses. In turn, Lenvima blocks kinases, a type of enzyme involved in blood vessel formation, tumor growth, and progression.
Both therapies are approved separately for treating several types of cancer, and their combination is approved for certain advanced endometrial cancers, which begin in the uterus.
The Keytruda-Lenvima combo also has received breakthrough therapy designation in the U.S. for treating advanced RCC. That designation is meant to expedite a therapy’s development and regulatory review.
The global, international CLEAR Phase 3 trial (NCT02811861), also known as Study 307 or KEYNOTE-581, is evaluating the safety and effectiveness of first-line treatment with Lenvima, in combination with either Keytruda or Afinitor, against standard treatment with Sutent in 1,069 adults with advanced RCC.
Participants — with prognoses ranging from favorable to intermediate and poor — were randomly assigned to receive either Lenvima plus Keytruda (355 patients), Lenvima plus Afinitor (357 participants), or Sutent (357 patients).
Lenvima, Afinitor, and Sutent all are given daily and orally, while Keytruda is administered directly into the bloodstream (intravenously) every three weeks.
The trial’s main goal was to assess whether either combination therapy was superior to standard treatment at extending the time patients lived without signs of disease progression. Secondary goals included overall survival, response rates, and safety measures.
At data cut-off, as of Aug. 28, 2020, patients had been followed up for a median of 26.6 months (more than two years). Treatment was ongoing in 40% of participants in the Keytruda-Lenvima group, 31.4% in the Lenvima-Afinitor group, and 18.8% in the Sutent group.
The results showed that the Keytruda combo prolonged the time patients lived without disease worsening by more than a year relative to Sutent (23.9 vs. 9.2 months), reducing the risk of disease progression or death by 61%.
Overall survival had not yet been reached for either treatment group, meaning that more than half of the participants were still alive at the data cut-off point. However, the Keytruda combo was found to also significantly extended patients’ survival, dropping the risk of death by 34%.
The Lenvima-Afinitor combination therapy also was significantly better than Sutent at delaying disease progression, but to a lesser extent, resulting in a 35% lower risk of disease worsening or death. No significant survival benefit was observed with the Afinitor combo.
The presence of an overall survival benefit with Lenvima in combination with Keytruda, but not with Afinitor, “confirms that an immune-checkpoint inhibitor–kinase inhibitor combination therapy is important in the first-line treatment of patients with advanced renal cell carcinoma,” the researchers wrote in the study.
Notably, these benefits were observed across all patient subgroups, regardless of age, sex, prognosis (favorable, intermediate, or poor), PD-L1 status (a predictor of responses to Keytruda), and the number of organs with metastasis.
In addition, a greater proportion (71%) of patients receiving the Keytruda combination responded to treatment, when compared with patients in the Afinitor (53.5%) and Sutent (36.1%) groups.
The Keytruda combo also led to considerably longer responses than the other two treatment regimens (25.8 months vs. 14.6–16.6 months).
The safety profile of each combination was consistent with that previously reported for each single therapy, and each combination. The most common treatment-related side effects (adverse events) in either group included diarrhea, high blood pressure, inflammation of the mouth, and fatigue.
Severe or worse treatment-related adverse events were more common among patients receiving either combination therapy (about 70% of patients) than in those given standard Sutent (58.8%).
“Continued efforts to improve outcomes in patients with advanced renal cell carcinoma are critical, considering that the number of people diagnosed with the disease has more than doubled over the last 50 years, and almost one-third of these patients are diagnosed at an advanced stage,” said Robert Motzer, MD, the head of the kidney cancer section at the Memorial Sloan Kettering Cancer Center, in New York.
CLEAR’s results “suggest that this combination has the potential to impact clinical practice for this type of devastating cancer,” Motzer added.
The study’s findings also “represent a significant milestone in our clinical research efforts in advanced renal cell carcinoma,” said Takashi Owa, PhD, vice president, chief of medicine creation, and chief discovery officer of the oncology business group at Eisai.
“Our progress thus far also reflects the significant contributions of dedicated patients, healthcare staff and researchers who continued to support this study during the global pandemic, to whom we extend our deepest gratitude,” Owa said.
