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MET Tyrosine Kinase Inhibitor Shows 'Encouraging' Efficacy in Phase III Kidney Cancer Trial

NEW YORK – An experimental small molecule MET tyrosine kinase inhibitor called savolitinib (AZD6094, HMPL-504, or volitinib under development from AstraZeneca) may be useful for treating patients with a subset of advanced papillary renal cell carcinoma (PRCC) kidney cancer that involves MET drivers, according to a new clinical study. The randomized Phase III clinical trial stopped enrollment early, though, due to new data from a comparator drug, sunitinib (Pfizer's Sutent).

"Although patient numbers and follow-up were limited, savolitinib demonstrated encouraging efficacy and an improved safety over sunitinib," explained Toni Choueiri, a medical oncologist at the Dana-Farber Cancer Institute, director of Dana-Farber's kidney cancer center, and a professor of medicine at Harvard Medical School, in an online presentation.

Choueiri presented the work in a video for the American Society of Clinical Oncology annual meeting, held online from Friday through Sunday.

Following promising preclinical, Phase I, and single-arm Phase II studies, his team set out to explore the possibility that savolitinib may improve progression-free survival for locally advanced or metastatic PRCC cases involving MET drivers. MET drivers consistently turn up in a subset of PRCC cases, Choueiri explained, and tend to coincide with large chromosomal rearrangements in the tumor.

Together with colleagues from the US, Canada, South Korea, France, and the UK, Choueiri randomized dozens of adult patients with MET-driven, advanced PRCC tumors to either standard doses of savolitinib or sunitinib, an oral treatment that targets a range of receptor tyrosine kinase enzymes. Sunitinib is approved by the US Food and Drug Administration for treating advanced kidney cancers such as advanced renal cell carcinoma, as well as for some forms of pancreatic or stomach cancer. PRCC represents some 15 percent of renal cell carcinoma cases.

While they intended to enroll around 180 patients for the new open-label randomized study, known as SAVOIR, the researchers closed enrollment early when data from other sources suggested sunifitinib had similar effects on time to disease recurrence in cases with or without MET drivers. 

"A crucial assumption for this study was that MET-driven status in PRCC is a negative predictor for treatment outcomes on sunitinib," Choueiri and his co-authors explained in a corresponding paper published in JAMA Oncology on Friday, noting that new data pointed to more favorable outcomes in sunitinib-treated cases with MET driver alterations.

Consequently, they explained, "it was decided that the SAVOIR study would not benefit from a reassessment of study size given the expected similarity in efficacy between the [two] treatment groups."

Up until enrollment stopped, the team had screened 254 cases and identified 60 patients with MET-driven tumors, randomizing 33 to savolitinib and 27 to sunilitinib. These were first-line treatments for most of the patients enrolled. Eligible MET driver mutations included MET or HGF amplifications, MET kinase domain alterations, or chromosome 7 gains, Choueiri said, with chromosome 7 gains turning up most frequently in SAVOIR.

The investigators saw a median progression-free survival time of 7 months in the savolitinib arm compared to 5.6 months in the sunitinib arm, though that difference was not statistically significant. The secondary endpoint of overall survival was not reached in the savolitinib group, Choueiri reported, but came in at 13.2 months in the sunitinib group.

When it came to overall response rate, the team saw 27 percent partial response in the patients treated with savolitinib and 7 percent in the sunitinib group. Severe adverse events such as anemia, hypertension, or liver function changes were documented in 42 percent of  savolitinib-treated patients and 81 percent of sunitinib-treated patients.

"We believe, in this study, that early termination of recruitment precludes a really definitive conclusion from being drawn, due to the small subset. However, based on this emerging data, further investigation of savolitinib as a treatment option for MET-driven PRCC is warranted," Choueiri said.