SAN FRANCISCO — Patients with newly diagnosed metastatic renal cell carcinoma (mRCC) lived about 3 months longer without disease progression with immunotherapy-based treatment rather than a targeted agent, a randomized trial showed.
In the subgroup of patients with PD-L1 positive tumors, initial treatment with atezolizumab (Tecentriq) and bevacizumab (Avastin) led to a median progression-free survival (PFS) of 11.2 months compared with 7.7 months for patients who received standard first-line treatment with sunitinib (Sutent). The intention-to-treat population had a median PFS of 11.2 months with the combination and 8.4 months with sunitinib, according to Robert Motzer, MD, of Memorial Sloan Kettering Cancer Center in New York City, and colleagues.
Median overall survival (OS) in the ITT population had yet to be reached, but trended in favor of the atezolizumab-bevacizumab arm. Additionally, more patients had objective responses with the combination, Motzer reported at a press briefing prior to the Genitourinary Cancers Symposium (GUCS).
“The response outcomes and encouraging immature overall survival results support improved efficacy for atezolizumab plus bevacizumab in patients with PD-L1 positive disease,” said Motzer. “Atezolizumab and bevacizumab had fewer high-grade treatment-related adverse events, low steroid use, and delayed symptom interference with daily life versus sunitinib.
“These study results support the consideration of atezolizumab and bevacizumab as a first-line treatment option for PD-L1 positive patients with advanced renal cell carcinoma.”
The results “represent an important breakthrough in cancer therapy,” said press briefing moderator Sumanta Pal, MD, of City of Hope in Duarte, California. For several years, oncologists have debated the relative merits of immunotherapy and targeted therapy as the preferred treatment for advanced RCC.
“This study, which is the first of its kind, points to a combination of both as being highly effective in delaying cancer growth, and there’s also an early trend toward improving survival,” said Pal. “The higher rate of complete response with bevacizumab and atezolizumab was also very encouraging. Achieving a complete response — total eradication of metastatic disease — is really the highest bar that we can strive for in this setting.”
Tolerability with the combination of targeted and immune therapies is another important piece of information from the study, he added. The side effect profile appeared to be superior, in some respects, to that of oral targeted agents used in the setting of mRCC.
“I would agree with Dr. Motzer that the data support consideration of atezolizumab and bevacizumab as a first-line option,” said Pal.
The trial involved 915 patients with previously untreated mRCC. Investigators in the international multicenter trial randomized the patients to the combination of atezolizumab and bevacizumab or to sunitinib, which has been standard of care as first-line therapy for mRCC for the past decade, Motzer noted. About 40% of the patients tested positive for PD-L1 expression, defined as >1% expression on tumor-infiltrating immune cells.
The trial had co-primary endpoints of investigator-assessed PFS in the PD-L1 positive subgroup and OS in the ITT population. Secondary endpoints included PFS in the ITT population, objective response rate, and duration of response.
Motzer reported findings from an analysis performed after a median follow-up of 15 months. The 3.5-month difference in PFS in the PD-L1 positive group was associated with a hazard ratio of 0.74 in favor of the atezolizumab-bevacizumab combination (95% CI 0.57-0.96, P=0.0217). Immature survival data showed a 19% reduction in the HR in favor of the combination, although the median had yet to be reached in either arm (95% CI 0.63-1.03, P=0.09).
Other endpoints consistently favored the combination treatment:
- PFS (ITT): 11.2 versus 8.4 months (HR 0.83, 95% CI 0.70-0.97, P=0.02)
- Survival (PD-L1+): Not reached versus 23.3 months (HR 0.68, 95% CI 0.46-1.00, P=0.05)
- Confirmed Response (PD-L1+): 43% versus 35%
- Confirmed Response (ITT): 37% versus 33%
- Complete Response (PD-L1+): 9% versus 4%
- Complete Response (ITT): 5% versus 2%
The combination of an immune checkpoint inhibitor and angiogenesis inhibitor resulted in a better safety profile. Patients randomized to sunitinib had higher rates of diarrhea, palmar/plantar erythrodysesthesia, hypertension, fatigue, dysgeusia, decreased appetite, mucositis, stomatitis, asthenia, and vomiting. The combination was associated with more proteinuria. Motzer reported that 16% of patients in the combination arm required systemic steroids to manage adverse events.
The safety and efficacy of atezolizumab and bevacizumab compared favorably with the dual immunotherapy combination of nivolumab (Opdivo) and ipilimumab (Yervoy), which also has been evaluated in advanced RCC, Pal noted.
“That [dual immunotherapy] regimen also demonstrated improved outcomes relative to sunitinib in patients with newly diagnosed metastatic kidney cancer, but nearly 60% of patients required steroids for management of side effects as compared with 16% in the study reported by Dr. Motzer.”
The study was supported by Roche/Genentech.
Motzer disclosed relevant relationships with Pfizer, Novartis, Eisai, Exelisix, Merck, GlaxoSmithKline, Bristol-Myers Squibb, and Roche Genentech.