Hutchison China MediTech — ASCO data set up fruquintinib for China launch

HCM and partner Lilly are developing fruquintinib as a potential best-in-class drug for it to compete in the global setting. In our view, FRESCO underpins the hypothesis that fruquintinib’s safety and efficacy profile could enable it to be positioned as best in class in China. Its profile internationally will be determined by global Phase III trials; however, data from FRESCO bode well.

Full data were presented at ASCO from HCM’s first pivotal Phase III trial (FRESCO), a China-based study, which evaluated fruquintinib, a VEGFR 1/2/3 inhibitor in third-line colorectal cancer patients. Colorectal cancer is believed to be one of the five most common cancers in both Chinese men and women, with an estimated 191.0 thousand deaths in China in 2015 (incidence of 376.3 thousand in 2015). Most Chinese CRC patients are treated with chemotherapy and few targeted therapies are approved, with limited salvage treatments in third line and above. If approved, fruquintinib could capture a significant portion of the market in these patients.

The FRESCO study randomised 416 patients (519 screened) 2:1 into fruquintinib (+ best standard of care [BSC] [n=278]) and placebo (+ BSC [N=138]) arms with an 80% powering to detect a hazard ratio of 0.7 (corresponding to a median OS improvement from 6.3 to nine months). Inclusion criteria included a range of factors, but notably patients had to have been diagnosed with metastatic stage IV colorectal cancer, have failed on two prior treatments (with fluoropyrimidine, oxaliplatin and irinotecan) and were allowed to have prior anti-VEGF or anti-EGFR targeted therapy. Eastern Cooperative Oncology Group (ECOG) status, a measure of patient health, demonstrated that 72.3% (n=201) of fruquintinib patients had an ECOG status of 1 and 27.7% had a status of ECOG 0 (placebo; ECOG 1:73.2% [n=101], ECOG 0:26.8% [n=37]). ECOG 0 patients are asymptomatic and ECOG 1 patients are symptomatic and restricted in strenuous physical activity, but can perform the majority of normal day-to-day functions (ECOG scale goes up to 5, which is death).

Both overall survival and progression-free survival (PFS) (Exhibits 1 and 2) demonstrated statistical significance over placebo, a notable clinical achievement when considering the difficult patient population in which fruquintinib was tested. Key points include:

These data compare favourably to both pivotal data from an international trial (CORRECT) with Bayer’s Stivarga (regorafenib) (a multi-kinase inhibitor targeting VEGFR 1,2 and 3, which is approved and sold in multiple countries) and to a subgroup analysis focused on Chinese patients from an Asian study (CONCUR). Both trials were in patients with previously treated metastatic colorectal cancer. Median overall survival on Stivarga in the CORRECT study was 6.4 months (95% CI, 5.8-7.3) versus 5.0 months (95% CI, 4.4-5.5) on placebo with a 0.77 hazard ratio (95% CI, 0.64-0.94). PFS was 2.0 months (95% CI, 1.9-2.3) vs 1.7 months on placebo (95% CI, 1.7-1.8).

Subgroup analysis of the CONCUR trial focused on Chinese patients (n=172, 112 on Stivarga, 60 on placebo). ECOG status of 1 was demonstrated in 72% of patients (n=81) and 0 in 28% of patients (31). OS in this Chinese patient subgroup was 8.4 months for Stivarga (vs 6.2 months on placebo, no CI given) with a hazard ratio of 0.56 (95% CI, 0.39-0.80). Median PFS was two months vs 1.7 on placebo (no CI given) with a hazard ratio of 0.32 (95% CI, 0.22-0.47).

Safety will be a key differentiator for fruquintinib as it looks to position itself in the Chinese market as a best-in-class product. Grade 3 and above adverse events (AEs) occurred in 61.1% (n=170) of patients receiving fruquintinib versus 19.7% (n=27) of patients in the placebo arm. Dose interruptions, a key indicator of tolerability, were 35.3% (n=98) in the fruquintinib arm and 10.2% (n=14) in the placebo arm, while treatment discontinuation occurred 15.1% (n=42) and 5.8% (n=8) in each arm respectively. The most common grade 3-5 adverse events were hypertension (21.2%, n=59), palmar-plantar erythrodysaesthesia/hand-foot syndrome (HFSR/PPE) (10.8%, n=30) and proteinuria (3.2%, n=9). All other grade 3-5 AEs occurred at a frequency below 3%, further reinforcing the selective nature of fruquintinib.

Due to varying patient demographics and standards of care, trial comparisons, while useful, can be complicated. Dose interruptions can be a key indicator for tolerability and can negatively affect the anti-angiogenic mode of action of VEGFR inhibitors.

In the CORRECT trial testing Stivarga (regorafenib), it was reported that 61% of patients receiving Stivarga required a dose interruption. Similar results occurred in the CONCUR trial, which demonstrated that 68.8% of patients had a dose interruption. In the CORRECT and CONCUR trials, treatment discontinuation occurred in 8.2% and 14% of the patients respectively.

In the CORRECT trial the most common grade >3 AEs were HFSR/PPE (17% vs 0% placebo), fatigue (15% vs 9% placebo), pain (9% vs 7% placebo), infection (9% vs 6% placebo), hypertension (8% vs <1% placebo), diarrhoea (8% vs 2% placebo), rash (6% vs >1% placebo) and mucositis (4% vs 0% placebo). All other grade > 3 AEs occurred below 3%. Stivarga also contains a black box warning for fatal hepatotoxicity (liver damage), which occurred in 1.6% of the metastatic CRC patient population (vs 0.4% on placebo).

In the Chinese patient subgroup analysis of the CONCUR trial, grade 3,4 and 5 AEs occurred in 52% (n=58), 8% (n=9) and 10% (n=11) of patients on Stivarga and 35% (n=21), 2% (n=1) and 10% (n=6) on placebo, respectively.

We believe that fruquintinib demonstrates comparable if not better efficacy than that of Stivarga, caveated by the fact that direct comparisons should be made cautiously. While severe side effects are apparent, mainly in the form of hypertension, these are manageable (eg hypertension controlling medication like beta blockers/ACE inhibitors and topical lotions for HFSR/PPE) and are a result of VEGFR inhibition. The lack of reported hepatotoxicity and a narrower side effect profile than Stivarga indicates that the majority of side effects are target based. We believe that this more controlled safety profile may be a key driver of sales. HCM has recently announced that the China FDA has accepted its new drug application (NDA) for fruquintinib in advanced CRC patients. This has triggered a milestone payment of RMB30.8m ($4.5m) to HCM from its partner Lilly. If approved, we anticipate a potential launch in China in 2018, where HCM’s partner Lilly will be responsible for sales and marketing.

In the US, a Phase I bridging study in Caucasian patients will initiate in 2017. This study should determine the dose required to take fruquintinib into US Phase II/II studies across its differing indications in preparation for a US NDA submission. Contingent on strong proof-of concept (POC) and Phase III results in fruquintinib clinical trials in China, Eli Lilly may exercise its option (once it receives the Phase III NSCLC data) to co-develop fruquintinib globally under the terms of the 2013 licence agreement. We expect fruquintinib to enter US Phase II/III trials regardless of whether Lilly exercises its option. We expect additional indications post the bridging study to be determined by a range of factors including combination potential and achievable market.

Presentations at ASCO from three collaborator trials utilising savolitinib (c-Met inhibitor) further reinforce its applicability in treating c-Met-driven patients. In an AstraZeneca (AZN) led trial (Abstract 9020), which tracked the response of osimertinib (Tagrisso) resistant NSCLC patients, 30% (7/23) of resistant patients were c-Met-driven (the largest driver of resistance and a significant new market opportunity); 3/3 of patients treated had a partial response when treated with savolitinib + EGFR TKI. Additional presentations included the initiation of an NIH/NCI-funded Phase II study (Abstract TPS4599), which is looking to compare sunitinib with three MET-directed therapies (including savolitinib) in PRCC. An update on the VIKTORY trial (Abstract 4020), testing savolitinib in preselected MET amp/overexpressed patients, was presented.

Phase II overall survival data on savolitinib in c-Met-driven PRCC later this year could support a US NDA application under breakthrough therapy designation, with potential to be HCM’s first internationally launched asset (we expect launch in the US in 2018 by partner AstraZeneca, which we assume will be under breakthrough therapy designation). Additionally, positive data from the ongoing multi-arm TATTON trial in second-line, EGFR-mutant lung cancer with savolitinib in combination with osimertinib (Tagrisso) could support a US NDA under breakthrough therapy designation for lung cancer. We anticipate the initiation of Phase III trials in PRCC and potentially NSLC (if a pivotal decision is made) in H217

A Phase II multi-centre trial of sulfatinib (VEGFR 1, 2 & 3, FGFR1, CSF-1R inhibitor) in advanced medullary thyroid cancer (MTC) and radioiodine-refractory differentiated thyroid cancer (DTC) is ongoing. As of 31 March 2017, a total of 20 patients have been enrolled and treated (total enrolment expected 30-50 patients). 16 of these patients are evaluable for efficacy evaluation, four (25%) of whom had confirmed partial response (PR) and the other 12 had stable disease (SD) including two unconfirmed PR. Objective response rates (include complete response and PR) in the MTC and DTC groups were 16.7% (n=1/6) and 33.3% (n=3/10) respectively. All 20 patients experienced at least one adverse event (AE) with 11 (55%) patients experiencing a grade 3 or above treatment-related AE; the most common grade >3 AEs were hypertension (20%) and proteinuria (20%) irrespective of causality. Three patients experienced a serious treatment-related AE, but there were no deaths due to treatment. Nine patients (45%) had a dose reduction and 15 patients (75%) had a dose interruption. Based on these promising initial data, we expect the trial to continue as planned with further data readouts in 2018.

Sulfatinib is currently in six ongoing trials: two Phase III registration trials (pancreatic NET and extra[non]-pancreatic NET), three Phase II trials (biliary tract carcinoma and thyroid cancer) and one Phase I crossover study in the US. A Phase II US study in NET is expected to initiate by year-end 2017. PFS data (top-line) from the China Phase III registration trials (SANET-p and SANET-ep) are anticipated in 2018. Positive data could lead to a China FDA filing in 2018/19. Sulfatinib is an unpartnered asset and HCM could reap the full economic benefit by launching this asset through its extensive manufacturing and distribution prescription drug business in China.