The programmed cell death 1 (PD-1) and PD-1 ligand (PD-L1) inhibitors "are going to disrupt the current treatment paradigm and will likely be the backbone of combination therapy," said Hans J. Hammers, MD, PhD.
Hans J. Hammers, MD, PhD
The programmed cell death 1 (PD-1) and PD-1 ligand (PD-L1) inhibitors “are going to disrupt the current treatment paradigm and will likely be the backbone of combination therapy,” said Hans J. Hammers, MD, PhD, during his presentation at the 16th Annual Society of Urologic Oncology, December 2-4, in Washington, DC.1
“There’s a plethora of PD-1 and PD-L1 inhibitors undergoing clinical development in renal cell carcinoma (RCC), with nivolumab the most advanced, followed by atezolizumab and avelumab,” he explained. Hammers, an assistant professor of oncology at the Sidney Kimmel Comprehensive Cancer Center and Johns Hopkins Medicine, in Baltimore, Maryland, provided an overview of some of the current research and posed some provocative questions to consider as the role of these agents in combination therapy is delineated.
He first highlighted data by Sharma et al, presented during the 2015 European Cancer Congress, that involved nivolumab versus everolimus in patients with advanced RCC. In that trial, CheckMate-025, the PD-1 inhibitor reduced the risk of death by 27% and showed an improved overall survival (OS) of 5.4 months. Findings were simultaneously published inThe New England Journal of Medicine.2,3
CheckMate-025 randomized 821 previously treated patients with advanced or metastatic clear-cell RCC in a 1:1 ratio to 3 mg/kg of intravenous (IV) nivolumab every 2 weeks or 10 mg of oral everolimus daily until progression or unacceptable toxicity. Prior treatment with one or two antiangiogenic treatment regimens for advanced or metastatic disease was required, along with evidence of disease progression within 6 months of enrollment.
In that trial, OS was the primary endpoint, while secondary outcome measures included objective response rate (ORR) and progression-free survival (PFS). At a minimum follow-up of 14 months, the median OS was 25.0 months with nivolumab versus 19.6 months with everolimus (HR, 0.73; 98.5% CI, 0.57-0.93;P= .002). The difference was statistically significant, meeting the criteria established in the trial design ofP≤.0148. The OS benefit was observed across patient subgroups, including cohorts defined by geography, Memorial Sloan Kettering Cancer Center prognostic score, and number of prior antiangiogenic regimens.
The trial was stopped early after meeting the primary OS endpoint, and eligible patients in the everolimus cohort were allowed to cross over and receive nivolumab in an open-label extension of the study.
Median PFS was 4.6 and 4.4 months in the nivolumab and everolimus arms, respectively (HR, 0.88; 95% CI, 0.75-1.03;P= .11). The researchers noted that there was a delayed separation of the PFS Kaplan-Meier curves. To further examine the results, they conducted an ad hoc sensitivity analysis of PFS in patients who had not progressed at 6 months. The median PFS in this cohort was 15.6 months with nivolumab versus 11.7 months with everolimus (HR, 0.64; 95% CI, 0.47-0.88).
“That was the elephant in the room,” said Hammers. “Everolimus, considered a ‘weak’ targeted therapy, and nivolumab, had similar time to PFS graphs. But starting at 9 months, there was a separation, which was driven by the response rates,” he said. Traditionally, response rates are not considered a primary endpoint, but in these patients, the response rates were very durable. “This allows us to identify the patient population that can derive the most benefit from these drugs.”
According to Hammers, toward the end of the curve for PFS, the part of the curve usually not considered for regulatory approval, a separation in PFS rates became significant. “We see that there is some lasting benefit over time, which is something that we do not fully understand yet. What we will want to know down the road, maybe 2 or 3 years from now, is are we going to see the tail end of that curve? Are there patients who are potentially cured?”
Hammers commented on the impressive response rates associated with nivolumab. “To see a response rate of 25% in a second- or third-line agent is impressive. To put that into context, the currently approved United States Food and Drug Administration (FDA) agent axitinib, indicated as second-line therapy for patients who have been previously treated with sunitinib, has a response rate around 11%.”
Perhaps the most compelling research involving PD-1 and PD-L1 inhibitors is their potential role in combination therapy. “If one immune checkpoint inhibitor works well, what about combining two different ones?” asked Hammers.
For patients with melanoma, this idea has been well documented.
In a double-blind study, CheckMate-069, the PD-1 inhibitor nivolumab plus the cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) inhibitor ipilimumab reduced the risk of progression or death by 60% compared with ipilimumab alone (HR, 0.40; 95% CI, 0.22-0.71;P<.002). With the combination, the ORR was 60% compared with 11% with ipilimumab alone in patients with BRAF wild-type melanoma.4As a result, the FDA granted an accelerated approval to the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) as a treatment for patients with BRAF V600 wild-type unresectable or metastatic melanoma.
Hammers also discussed research involving the combination of nivolumab with a VEGF pathway inhibitor. The VEGF receptor inhibitors sunitinib and pazopanib are standard of care in the treatment of patients with metastatic RCC; however, their antitumor effects are not durable.
At the European Society for Medical Oncology 2014, Amin and colleagues reported preliminary results of a phase I trial of nivolumab plus either sunitinib (S+N) or pazopanib (P+N) in patients with metastatic RCC.5In this study, patients received either sunitinib 50 mg, 4 weeks on and 2 weeks off, or pazopanib 800 mg daily. Previously treated patients received IV nivolumab 2 mg/kg and were subsequently titrated up to 5 mg/kg IV every 3 weeks.
Overall, 7 patients were each initially treated with sunitinib plus nivolumab 2 mg/kg and 5 mg/kg, and this cohort was then expanded to an additional 19 treatment-naïve patients (total, n = 33) based on no reports of dose-limiting toxicities.
In the P+N arm, 4 dose-limiting toxicities, including elevations of ALT/AST in 3 patients and fatigue in 1 patient, were observed, leading to closure of this arm. Grade 3/4 treatment-related adverse events were reported in 27 of 33 patients (82%) and in 14 of 20 patients (70%) in the S+N and P+N groups, respectively. The researchers concluded that combination therapy with sunitinib plus nivolumab showed encouraging antitumor activity and was associated with a manageable safety profile in patients with advanced RCC. They also noted that the combination therapy resulted in responses that were higher than previously reported for monotherapy of either agent. However, they noted that the combination of pazopanib plus nivolumab was not a feasible treatment option because of dose-limiting toxicities.
The final study Hammers highlighted was a phase III study investigating atezolizumab in combination with bevacizumab versus sunitinib (NCTNCT02420821).6The trial involves patients who have not received prior systemic active or experimental therapy, either in the adjuvant or metastatic setting.
The primary outcome is PFS, with secondary outcome measures of OS, ORR, and time-to-deterioration in patient-reported tiredness severity score.