SHANGHAI – Hutchison China Meditech Ltd. (Chi-Med) and its partner, Astrazeneca plc, of London, shared phase II safety and efficacy data for savolitinib in patients with papillary renal cell carcinoma (PRCC), a fatal form of kidney cancer. Presented over the weekend at the Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology (ASCO) held in Orlando, Fla., the study concluded savolitinib to be generally well-tolerated with antitumor activity in Met-driven PRCC patients.

The single-arm phase II study conducted in 22 centers in the U.S., Canada, U.K. and Spain is considered to be the largest global prospective clinical trial in PRCC, having studied savolitinib – a selective mesenchymal epithelial transition (Met) inhibitor (IC50 of 4 nM) – in 109 patients with locally advanced or metastatic PRCC. Plans are underway to kick off a phase III trial in the coming months.

Savolitinib was designed to address issues observed in the clinic with first-generation c-Met (cellular mesenchymal-epithelial transition factor) inhibitors, including renal toxicity. While PRCC affects about 6,000 to 9,000 people each year in the U.S. – a relatively small population – savolitinib is also being studied in gastric cancer and various forms of lung cancer, including as a second-line therapy for VEGF-TKI refractory non-small-cell lung cancer (NSCLC), for which pivotal data are expected this quarter. If successful, it would put savolitinib ahead of the pack of potential Met-targeted contenders. (See BioWorld Today, June 22, 2016, and Jan. 20, 2017.)

In addition, on Monday, Chi-Med announced it kicked off a phase II trial in China in patients with locally advanced or metastatic pulmonary sarcomatoid carcinoma (PSC) harboring Met gene alterations. PSC is a poorly understood, rare subtype of lung cancer that has no approved medication.

Similarly, PRCC patients have no approved treatment options and the disease lacks a clear standard of care, causing the National Comprehensive Cancer Network guidelines to recommend enrolling patients in clinical trials for first-line systemic therapy.

"There is a clear unmet medical need in PRCC," said Toni Choueiri, director of the Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute. "The dataset from this phase II study is compelling, with a very clear efficacy signal in Met-driven patients and an encouraging long duration of response, while remaining very well-tolerated."

The primary objective of the PRCC phase II study was to assess the objective response rate to savolitinib in all patients with PRCC and by Met status. Secondary objectives included change in target lesion tumor size from baseline, progression-free survival (PFS) and duration of response.

Patients were dosed with 600 mg of savolitinib daily until disease progression.

A molecularly driven patient selection approach was taken with the aid of a companion diagnostic to identify Met-driven patients.

In the study sample, it was found that 44 patients (40 percent) were Met-driven, 46 patients (42 percent) were Met-independent and Met status was unknown for the remaining 19 patients.

In the Met-driven PRCC sample, 27 patients (61 percent) experienced some tumor shrinkage, compared to nine Met-independent patients (20 percent). A partial response was seen in 18 percent of Met-driven patients (eight out of 44). In addition, 43 patients achieved stable disease, while 48 saw progressive disease. Ten patients were not evaluable for response.

In the Met-driven group, it took 6.2 months for tumor progression to occur in half of the patients while in the non-Met group median PFS occurred after 1.4 months.

Overall survival data are still not mature, and according to Christian Hogg, Chi-Med CEO, those results will be released at the ASCO annual meeting.

Hogg said he is encouraged by the duration of the response in the Met-driven patients that saw partial responses (PRs). Of the eight patients exhibiting PR, six were still responding to treatment at data cut-off, with a duration of response between 2.4 months and 16.4 months.

Hogg also noted that savolitinib is better tolerated than the multikinase inhibitors that are often prescribed to PRCC patients. "It [savolitinib] is a hugely different drug than what is available for renal cell carcinoma at the moment," Hogg pointed out.

Adverse events (AEs) of a greater than grade 3 toxicity affected 21 percent of patients on the savolitinib trial, while 9 percent of patients suffered AEs that led to discontinuation. The most common side effects included nausea, fatigue, edema and abnormal liver function tests.

One death did occur due to hepatic encephalopathy and the drug's inhibition of a hepatotoxicity growth factor receptor involved in liver function. A treatment protocol has been put in place to monitor liver enzyme levels and reduce drug amounts when necessary.

BIOMARKER STUDY FOR BREAKTHROUGH STATUS?

Over the course of 2017, Chi-Med and Astrazeneca also are conducting a comprehensive molecular epidemiology study of approximately 300 PRCC patient samples to further understand the correlations between c-Met alterations and patient outcomes, including any predictive biomarkers. That is the first such biomarker study in PRCC.

"Savolitinib in c-Met-driven patients is providing meaningful benefit," Hogg told BioWorld Today. "Now, the next question is, and what we hope to prove to the regulators, is that Met is a negative prognostic.

"If we are able to show, based on the epidemiology study, that we have answered the question, and that the clear benefits that these Met-driven patients enjoy are because of savolitinib, given that this is a difficult patient population, we think we can submit for breakthrough designation."

However, there is also a chance that the phase IIb extension of the TATTON trial for savolitinib in NSCLC as a combination therapy with Tagrisso (osimertinib) or Iressa (gefitinib) in 25 EGFR-mutant lung cancer patients could jump to the front of the line. (See BioWorld Today, June 22, 2016.)

"When you talk about breakthrough therapy designation and unmet medical needs, the Tagrisso combination [with savolitinib] has the potential to overtake the other [PRCC trial], subject to the phase IIb data being good," said Hogg.

Savolitinib is one of nine small-molecule oncology and inflammation candidates in Hutchison's pipeline, but stands out as one of two partnered with big pharma, the other being fruquintinib, a selective inhibitor of the VEGFR tyrosine kinase partnered with Eli Lilly and Co., of Indianapolis.

Those partnership deals have helped finance Hutchison's global ambitions now with 24 clinical trials ongoing in Greater China, North America, Europe and Australia.