1. Goodwin, Peter M.

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MUNICH-A doubling of progression-free survival (PFS) and objective response rate (ORR) was observed in patients who had their previously untreated advanced renal cell cancer (RCC) treated with a combination of the vascular endothelial growth factor (VEGF) inhibitor axitinib plus the anti-PD-L1 avelumab in comparison with those receiving standard sunitinib anti-VEGF therapy in the randomized phase III JAVELIN Renal 101 clinical trial. Findings were reported at the 2018 ESMO Annual Congress.

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"The progression-free survival was so robust, the objective response rate was robust, [and] the safety profile was favorable that [this] warrants this combination as a new standard of care in patients with advanced kidney cancer," said lead investigator Robert J. Motzer, MD, PhD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York.


Study Details, Key Findings

The study randomized 886 patients-irrespective of prognostic subgroups-to treatment with a combination of IV avelumab every 2 weeks plus daily oral axitinib or to monotherapy with daily oral sunitinib (4 weeks taking the drugs followed by 2 weeks without it).


The primary outcomes were PFS and overall survival (OS). Nearly three-quarters of all patients had adverse events of at least grade 3-irrespective of treatment arm. In the combination arm, a quarter of the patients discontinued treatment due to side effects as compared with one in eight patients treated with sunitinib.


The PFS among 270 patients positive for the PD-L1 molecule treated with the combination was 13.8 months-compared with 7.2 months in the sunitinib arm (HR of 0.61 with a significant p-value of less than 0.0001).


In 442 patients grouped together-including PD-L1 positive and negative-the PFS was also 13.8 months among patients on the combination treatment compared with 8.6 months in those who received sunitinib (HR=0.69 and a significant p-value of 0.0001).


In patients positive for PD-L1, the ORR was 55.2 percent to the combination compared with 25.5 percent among those on sunitinib treatment. In patients assessed irrespective of PD-L1, the ORR was 51.4 percent in those treated with the combination compared with 25.7 percent for those taking sunitinib.


Motzer said OS had not been measured because there had been too few survival events and that it would need to be analyzed in the future.


When asked why PD-L1 positivity had not made a difference, he suggested one reason was testing could give false-negative results. "Tumors are heterogeneous. PD-L1 expression can change over time. I do think the drugs are hitting the target. I think it's more of an issue with regard to our techniques for staining."


Both VEGF tyrosine kinase inhibitors (TKIs) and checkpoint inhibitors had single agent activity in kidney cancer and there had been a "strong rationale" for combining them, according to Motzer.


"In addition to the anti-angiogenic effect of drugs like sunitinib and axitinib, they also change the immune environment around the tumor. So they 'prime' the tumor for the checkpoint inhibitor to come in and alert [the] immune system to the cancer. There is a synergism between the two," he explained.


Clinical Implications

Motzer saw the JAVELIN results as endorsement of the value of the combination regimen. "To me it indicates that we don't necessarily have to test [for] PD-L1 in patients' tumors. This regimen would be offered to all patients with advanced RCC regardless of their PD-L1 staining."


When asked if recent progress with several promising new treatment options for advanced RCC had been potentially confusing for clinicians, Motzer said there was a need for options because "one size did not fit all."


In his own practice, he preferred to have a clinical trial option for each patient as well as a standard-of-care option. "Right now the standard-of-care options are either ipilimumab plus nivolumab or tyrosine kinase inhibitors like sunitinib and cabozantinib-it's an individual approach," he said.


The JAVELIN Renal 101 findings were proof of principle that combining a TKI with immunotherapy gave high response rates and long PFS, noted Motzer. "This looks like a very promising approach. The progress that we've made in kidney cancer is amazing and doctors need to be aware of the options so they can offer their patients the best chance for a long survival."


Thomas Powles, MBBS, MRCP, MD, consultant oncologist at Barts Cancer Centre, St. Bartholomews Hospital in London, commented that the results were eye-catching.


"The response rates are twice as good as previous standards of care and progression-free survival is entering into very impressive territory for a randomized trial," he said. But Powles added a note of caution: "This approach involves giving combinations of most active agents upfront. Therefore there is uncertainty around whether this will translate into a similarly impressive [overall] survival signal-as seen with other immunotherapy combinations."


Peter M. Goodwin is a contributing writer.