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

ASCO Annual Meeting 2015 Highlights

Researchers identified a new biomarker called mismatch repair (MMR) deficiency, which predicts superior response to anti-PD1 therapy. The ORR was 62% in MMR-deficient patients compared with 0% in MMR-proficient patients. Tumors with MMR deficiency harbor many more mutations than tumors without such repair defects. Tumors with more mutations are more likely to be recognized as foreign by the immune system.

Nivolumab showed promising activity in advanced liver cancer in a Phase I/II trial. The ORR in 42 evaluable patients was 19%, including two with complete responses. 68% of patients had previously received sorafenib. The overall survival rate at 12 months was 62% with nivolumab. Sorafenib is currently the only FDA-approved systemic treatment for advanced liver cancer. The response rate with sorafenib in this setting is only 2%.

About one year ago, Puma Biotechnology (NASDAQ: PBYI) skyrocketed 295% after reporting the top-line results from the Phase III trial (ExteNET) of neratinib in HER2+ early breast cancer. At the ASCO2015, the company provides a primary analysis at 2 years of ExteNET trial. IDFS in the neratinib arm was 93.9% compared to 91.6% for placebo. The absolute difference of only 2.3% was lower than the market expected. Moreover, the drug caused high rates of Grade ≥ 3 diarrhea (40%).

Oncothyreon’s (NASDAQ: ONTY) ONT-380, in combination with capecitabine/trastuzumab, showed promising results in HER2+ metastatic breast cancer patients previously treated with trastuzumab and T-DM1. The ORR in 27 evaluable patients was 52%. In another Phase Ib trial, 22 breast cancer patients with CNS metastases were treated with ONT-380 plus T-DM1 or ONT-380 plus capecitabine/trastuzumab. One patient had a complete response; four had a partial response and nine has a stable disease. ONT-380 selectively inhibits HER2 without significant inhibition of EGFR, avoiding EGFR-like side effects. No Grade ≥ 3 diarrhea has been seen.

In April 2015, Clovis Oncology (NASDAQ: CLVS) received Breakthrough Therapy designation for PARP inhibitor rucaparib for the treatment of BRCA-mutated ovarian cancer. At the ASCO2015, the company posted positive data from a Phase II trial. The ORR in 32 patients was 82%. The median PFS was 9.4 months. Rucaparib appears superior to AstraZeneca’s olaparib. The accelerated approval of olaparib is based on an ORR of 34% and a median DOR of 7.9 months.

ImmunoGen’s (NASDAQ: IMGN) IMGN853 demonstrated encouraging clinical activity in heavily pretreated patients with FRα positive platinum-resistant ovarian cancer. The ORR was 53% (n=9/17) which included one complete response and eight partial responses. IMGN853 is antibody-drug conjugate that comprises an anti-FRα antibody conjugated with DM4.