CSCO Annual Meeting 2015 Highlights: anlotinib and fruquintinib

I am at the 2015 Annual Meeting of Chinese Society of Clinical Oncology in Xiamen, Fujian Province today. Here are some takeaways.

Abstract BI018: Anlotinib provides significant survival benefit in advanlced NSCLC
Anlotinib (AL3818) is a multi-target tyrosine kinase inhibitor (TKI) developed by Chia Tai Tianqing. In a Phase II trial (CTR20130315), the drug provides significant survival benefit in NSCLC (non-small cell lung cancer). The trial enrolled 117 patients with advanced NSCLC who had failed two previous treatments, 60 patients with anlotinib and 57 patients with placebo. Anlotinib significantly improved median PFS (4.8 vs 1.2 months, p<0.0001) and median OS (10.3 vs 6.3 months, p=0.075). The drug also improved ORR (13.3% vs 0.0%) and DCR (93.33% vs 47.37%). More patients experienced Grade 3/4 treatment-related adverse events with anlotinib (21.67% vs 5.26%). The most commonly reported treatment-related adverse events were hand-foot syndrome and hypertension.

Abstract DI005: Fruquintinib provides significant survival benefit in mCRC
Hutchison MediPharma presents Phase II (CTR20130968) results of fruquintinib (HMPL-013) in metastatic colorectal cancer (mCRC) at the CSCO2015. A total of 71 patients who had failed at least 2 prior lines of chemotherapy were enrolled in the trial, with 47 in the fruquintinib arm and 24 in the placebo arm, respectively. Fruquintinib improved median PFS (4.7 vs 1.0 months, p<0.0001) and median OS (7.6 vs 5.5 months). There was one response reported in the fruquintinib arm. The DCR in the fruquintinib arm was 68.1%, compared with 20.8% in the placebo arm. The most commonly reported treatment-related adverse events were hand-foot syndrome and hypertension. Dose interruption and dose reduction due to adverse events was reported to 51.3% in the fruquintinib arm.

Anlotinib is a cediranib me-too first discovered by Advenchen Laboratories (patent: WO2008112407). The company created a broad TKIs portfolio and established collaboration with Chinese Big Pharma.

TKI candidates discovered by Advenchen Laboratories

Program Target Indication Stage Partner
apatinib (YN968D1) VEGFR gastric cancer Approved Hengrui Medcine
HCC Phase III Hengrui Medcine
NSCLC Phase III Hengrui Medcine
lucitanib (AL3810) FGFR, VEGFR solid tumors Phase I SFFT (China)
NSCLC Phase II Clovis Oncology (US)
breast cancer Phase II Clovis Oncology (US)
anlotinib (AL3818) VEGFR, PDGFR, etc. CRC Phase II Chia Tai Tianqing
NSCLC Phase II Chia Tai Tianqing
RCC Phase II Chia Tai Tianqing
STS Phase II Chia Tai Tianqing
simotinib (AL6802) EGFR solid tumors Phase I Simcere

Tianqing’s NSCLC results are encouraging, but a Phase III trial is warranted to confirm these findings. Bayer once tested multi-target TKI sorafenib in NSCLC in a Phase III trial (MISSION). Sorafenib failed to demonstrated improvement in OS, though an improvement in PFS was observed.

The Phase II results of fruquintinib are not as good as the Phase Ib data presented at the ASCO2014. In the previous Phase Ib trial, 23.2% (13/56) of patents achieved a partial response or a minor response. The DCR was 80.4%, and the 9-month survial rate was 50%. In the Phase II trial, however, response rate dropped to 2.1%, the DCR dropped to 68.1%, and the median OS dropped to 6.3 months.

Regorafenib, another multi-target TKI, has been approved for the treatment of mCRC. According to the CONCUR trial in Asia, regorafenib significantly improved median PFS (3.2 vs 1.7 months, p<0.0001) and median OS (8.8 vs 6.3 months, p=0.002). The DCR also favored regorafenib over placebo (52% vs 7%). The most commonly reported treatment-related adverse events were hand-foot syndrome and hypertension. The efficacy and safety of fruquintinib and regorafenib are extremely similar.

Hengrui and Tianqing are developing their own TKIs for the treatment of mCRC. Hengrui presented Phase II results of famitinib at the ASCO2015 Gastrointestinal Cancers Symposium. The drug significantly improved median PFS (2.8 vs 1.5 months, p=0.004) and DCR (59.8% vs 31.4%). However, no difference in OS (7.5 vs 7.6 months) and ORR (2.2% vs 0.0%) was observed. The incidences of serious adverse events for the famitinib and placebo groups were 11.11% and 9.09%, respectively. The safety profile of famitinib seems better than competitors. Hengrui is running a Phase III trial to further evaluate the drug.

Tianqing is testing anlotinib in a large Phase II trial. Tianqing can use the Phase II results to file NDA. If all four TKIs are approved, these drugs have to compete with each other.

Phase II/III TKIs for the third-line treatment of mCRC

Company Trials ID Enrollment Start Date
regorafenib Bayer CTR20131694 163 patients 2012-04-29
famitinib Hengrui Medcine CTR20150185 540 patients 2015-03-10
fruquintinib Hutchison MediPharma CTR20140758 400 patients 2014-12-08
anlotinib Chia Tai Tianqing CTR20140777 450 patients 2014-12-09
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