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Immunotherapy/VEGF Inhibitor Combos to Define Frontline Standard in mRCC

Caroline Seymour
Published: Monday, Jan 14, 2019

Dr. Sumanta Kumar Pal
Sumanta Kumar Pal, MD
VEGF TKIs have long defined the frontline standard of care in metastatic renal cell carcinoma (mRCC), but several promising trials evaluating their use in combination with immunotherapy agents may redefine the frontline setting in this patient population.

"Sunitinib (Sutent) has really served as the cornerstone of therapy for a very long time," said Sumanta K. Pal, in a presentation during the 2018 OncLive® State of the Science Summit™ on Genitourinary Cancers, of the TKI that was approved by the FDA in 2006.

Now, the TKI has become the comparator arm against newer combinations of TKIs and immunotherapy agents.

At the meeting, Pal, a medical oncologist at City of Hope, highlighted the different combination regimens that are making headlines in the treatment of these patients.

One FDA-approved combination immunotherapy option is nivolumab (Opdivo) and ipilimumab (Yervoy). As assessed in the CheckMate-214 trial, patients with intermediate- and poor-risk disease were randomized 1:1 to receive either 50 mg of sunitinib on a 4-weeks-on, 2-weeks-off schedule or 3 mg/kg of nivolumab and 1 mg/kg of ipilimumab every 3 weeks for 4 doses, followed by nivolumab every 2 weeks.

The combination resulted in a significant improvement in overall survival (OS) compared with sunitinib in patients with intermediate- and poor-risk disease, which was approximately 75% of the intent-to-treat (ITT) population. At the time of data cutoff, in this group, the median overall survival (OS) had not yet been reached in the combination arm versus 26 months in the sunitinib arm (HR, 0.63; 99.8% CI, 0.44-0.89; P <.0001).1

"It's important to note that nivolumab and ipilimumab does not represent a standard for patients with good-risk renal cell carcinoma—[which includes] patients with normal calcium levels, who have a long latency from the time at which they were originally diagnosed to the time they start systemic therapy," noted Pal.

In patients with good-risk disease, only 29% responded to the combination compared with 52% with sunitinib. Additionally, progression-free survival (PFS) was notably superior at 25.1 months with sunitinib versus 15.3 months with the combination.

"We often think of immunotherapy as being sort of a kinder, gentler approach, but about one-quarter of patients discontinued the combination of nivolumab and ipilimumab on account of drug toxicity," Pal added.

At a median follow-up of 25.2 months, 24% of all patients discontinued the combination compared with 12% with sunitinib due to drug toxicity. Of those who received the combination, 60% were given corticosteroids to counteract a resulting adverse event (AE).

PD-L1 expression served as an exploratory endpoint of the study. PD-L1 ≥1% was indicative of a greater PFS in patients with poor- and intermediate-risk disease. No substantial difference was observed between arms in patients who were PD-L1 negative. OS benefit was observed relative to sunitinib in patients with both PD-L1 <1% and PD-L1 ≥1%. Accounting for other clinical factors, PD-L1 can be used to select the regimen that is best suited for patients, explained Pal.

The combination of bevacizumab (Avastin) and atezolizumab (Tecentriq) is another regimen up for consideration, explained Pal—data for which were presented at the 2018 Genitourinary Cancers Symposium. Although a similar patient population was enrolled in the phase III IMmotion151 trial as the CheckMate-214 study, a focus was put on those with sarcomatoid histology based on positive phase I/II data in that same subset.

Patients enrolled in the trial were randomized 1:1 to receive either 1200 mg of atezolizumab and 15 mg/kg of bevacizumab, or the standard dose of sunitinib. The primary endpoint was PFS in PD-L1–positive patients based on investigator assessed response. Median PFS rates in both the PD-L1–positive and ITT populations were superior with the combination.

At a median follow-up of 15 months in the PD-L1–positive group, the median PFS rates were 11.2 months (95% CI, 8.9-15.0) and 7.7 months (95% CI, 6.8-9.7) with the combination and sunitinib, respectively (HR, 0.74; 95% CI, 0.57-0.96; P = .0217).2 In the ITT population, the median PFS with atezolizumab/bevacizumab was 11.2 months (95% CI, 9.6-13.3) versus 8.4 months (95% CI, 7.5-9.7) with sunitinib (HR, 0.83; 95% CI, 0.70-0.97; P = .0219).

In the ITT analysis, the ORR was 37% with atezolizumab/bevacizumab versus 33% for sunitinib. The CR rates were 5% and 2%, in the combination and sunitinib groups, respectively. The addition of immunotherapy to bevacizumab resulted in a higher CR in the PD-L1–positive group than what was observed with a VEGF TKI alone at 9% and 4%, respectively.

Approximately 16% of patients on the combination required interventional steroids. Additionally, the discontinuation rate due to AEs was lower with the combination compared with sunitinib. However, because OS data remain immature, clinicians should hold off on prescribing the combination to patients, said Pal.

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