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MUNICH -- An immuno-targeted therapy combination significantly improved progression-free survival (PFS) and response rate in newly diagnosed advanced renal cell carcinoma as compared with a current standard of care, a randomized trial showed.

Patients treated with avelumab (Bavencio) and axitinib (Inlyta) had a median PFS of 13.8 months as compared with 7.2 months with sunitinib (Sutent). The combination led to twice as many objective responses, irrespective of tumor PD-L1 expression status.

The benefits of the combination came with a favorable safety profile, Robert Motzer, MD, of Memorial Sloan Kettering Cancer Center in New York City, reported here at the (ESMO) congress.

"These results support avelumab plus axitinib as a new first-line standard of care for patients with advanced renal cell carcinoma," said Motzer.

"I don't think it will be necessary to test patients for PD-L1 status before using this combination," he added in response to a question.

The results continued the steady progress in the treatment of RCC that started with the introduction of targeted agents, said John Haanen, MD, of The Netherlands Cancer Institute in Amsterdam. The combination of avelumab and axitinib clearly represents an improvement over single-agent sunitinib, but with the positive results comes a new question, he said: What to offer patients who progress during or after treatment with the combination or do not respond to it?

A definitive assessment of the combination's role in treating advanced RCC should await the survival analysis, Viktor Grunwald, MD, of the West-German Cancer Center in Essen, said during a formal discussion of the avelumab-axitinib study, known as . Data on health-related quality of life is also needed to inform decision-making about the combination.

Acknowledging the "convincing" PFS data, Grunwald nonetheless questioned whether upfront combination therapy is better than sequential treatment. Moreover, the combination will likely face competition almost immediately.

As reported , nivolumab (Opdivo) plus ipilimumab (Yervoy) demonstrated a survival advantage over sunitinib in patients with untreated intermediate- and high-risk advanced RCC. Also reported earlier this year, the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) improved PFS and overall survival versus sunitinib among patients with newly diagnosed advanced RCC.

On the , Merck stole some of the thunder from the JAVELIN Renal 101 presentation by announcing "statistically significant and clinically meaningful improvement" in PFS and overall survival with the combination of pembrolizumab (Keytruda) and axitinib versus sunitinib in untreated advanced/metastatic RCC.

Since its approval in 2006, sunitinib has been a first-line standard of care for advanced/metastatic RCC. Other agents have approved first-line indications, including immune checkpoint inhibitors and other drugs in the tyrosine kinase inhibitor (TKI) class that includes sunitinib and axitinib.

Seeking to improve response rates and survival in RCC, investigators increasingly have examined combinations with different mechanisms of action. Avelumab, a PD-L1 inhibitor, stimulates an antitumor immune response, and axitinib blocks tumor angiogenesis, Motzer noted. Sunitinib is at a disadvantage as a "partner" in combination therapy because of its toxicity profile, in particular liver toxicity, he added. Axitinib is less toxic, making it a better partner for combination strategies.

Preclinical studies showed that simultaneous inhibition of PD-1/PD-L1 and vascular endothelial growth factor (axitinib's primary target) had synergistic antitumor activity. A small of the avelumab-axitinib combination demonstrated a 58% objective response rate with manageable toxicity in patients with advanced RCC. The response rate was higher in patients with PD-L1+ tumors.

The trial provided the basis for the international, randomized, phase III JAVELIN Renal 101 trial, which involved 886 patients with newly diagnosed advanced RCC.The trial had coprimary endpoints: PFS and overall survival (determined by independent review) in the subgroup of patients with PD-L1+ tumors, who accounted for 63% of the study population.

Baseline characteristics of the two treatment groups were similar, between patients with PD-L1+ or PD-L1- tumors.

The initial data analysis showed that treatment with the combination reduced the hazard for death or disease progression by 39% in patients with PD-L1+ tumors (95% CI 0.475-0.790, P<0.0001). The 13.8-month median PFS in the combination arm is expected to increase over time, as the upper limit of the 95% confidence intervals could not be estimated, said Motzer.

Calculations for the overall population produced an identical median PFS of 13.8 months in the combination arm and 8.4 months in the sunitinib group (HR 0.69, 95% CI 0.5o63-0.840, P=0.0001). Once again, the upper limit of the 95% confidence intervals could not be estimated.

"This finding supports the outcome of the primary analysis and shows benefit regardless of PD-L1 status," said Motzer.

The combination led to objective responses in 55% of patients with PD-L1+ tumors versus 26% with sunitinib. A similar difference emerged from an analysis of objective response rate in all 886 patients (51% versus 26%).

Overall survival data remained immature, and the median could not be estimated for either treatment group. The next survival analysis will occur during the first half of 2019, Motzer said.

Grade 3/4 adverse events occurred in about half of each treatment group. The incidence of grade 4 adverse events was 4% with the combination and 7% with sunitinib. Rates of discontinuation because of adverse events were 4% in the combination arm and 8% in the sunitinib group. Immune-related adverse events occurred in 38% of patients treated with avelumab and axitinib, the most common being hypothyroidism (21%). Grade 3/4 immune events were uncommon (~1%).

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