Anlotinib confers PFS, but not OS, benefit in metastatic CRC

In patients with metastatic colorectal cancer (mCRC), the addition of anlotinib to best supportive care did not confer overall survival (OS) benefit, though there was improvement in progression-free survival (PFS), according to results of the phase III ALTER0703 trial presented at ASCO GI 2021.

“Anlotinib, a multi-target tyrosine kinase inhibitor, could substantially prolong median PFS with tolerable and manageable toxicity for Chinese [patients] with mCRC,” said study author Dr Yihebali Chi from the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China.

Chi and co-authors enrolled adult patients with mCRC from 33 hospitals in China who had previously been treated with ≥2 prior lines of chemotherapy and who had an ECOG performance status of 0–1. The patients were randomized 2:1 to receive oral anlotinib (12 mg/day on days 1–14 Q3W; n=282) or placebo (n=137) in addition to best supportive care until disease progression or intolerable toxicity.

Baseline characteristics were comparable between patients in the anlotinib and placebo groups including age (median 57.5 vs 55.0 years), male (62.8 percent vs 66.4 percent), RAS/BRAF wildtype status (36.5 percent vs 33.6 percent), and presence of liver metastases (76.6 percent vs 70.1 percent). About 31 percent of each group had received prior anti-VEGF therapy.

Patients in the anlotinib and placebo groups were followed up for a median 31.0 and 31.8 months, respectively.

OS did not significantly differ between patients assigned to anlotinib and placebo (median 8.57 vs 7.16 months; hazard ratio [HR], 1.02, 95 percent confidence interval [CI], 0.82–1.27; p=0.87). [ASCO GI 2021, abstract 65]

Subgroup analysis of the OS results suggested that patients who were KRAS/NRAS/BRAF wildtype would incur benefit from anlotinib vs placebo (HR, 0.68) as opposed to those with these mutations (HR, 1.10; p_interaction=0.0005). In patients who were RAS/BRAF wildtype, median OS was 11.0 vs 6.7 months for those on anlotinib vs placebo.

PFS was significantly improved in the anlotinib vs placebo group (median 4.14 vs 1.45 months; HR, 0.34, 95 percent CI, 0.27–0.43; p<0.0001).

There was a trend toward a greater objective response rate (ORR) with anlotinib than placebo (4.26 percent vs 0.73 percent; odds ratio [OR], 0.165, 95 percent CI, 0.021–1.286; p=0.069), as well as a significantly improved disease control rate (75.9 percent vs 30.7 percent; OR, 0.140, 95 percent CI, 0.089–0.221; p<0.0001).

The ORR was driven by the 12 and one patient in the anlotinib and placebo groups, respectively, who demonstrated partial response, with no patients in either group having a complete response at time of analysis. About 72 and 30 percent, respectively, had stable disease, while about 17 and 53 percent, respectively, had progressive disease.

Grade ≥3 adverse events (AEs) were more common in anlotinib than placebo recipients (66.7 percent vs 35.8 percent), as were grade ≥3 treatment-related AEs (52.5 percent vs 19.7 percent) and treatment-related serious AEs (12.4 percent vs 7.3 percent). AEs led to treatment dose reductions in 18.4 and 0.7 percent of anlotinib and placebo recipients, respectively.

The most common grade ≥3 anlotinib-related AEs were hypertension (20.9 percent), increased gamma-glutamyl transferase levels (7.1 percent), and hand-foot syndrome (6.4 percent), all of which recovered following dose reduction. There were two incidents of grade 5 treatment-related AEs (haemorrhage) in anlotinib recipients. There were no unexpected AEs.

Almost 34 percent (33.7 percent) and 50.4 percent of patients in the anlotinib and placebo groups, respectively, received subsequent anticancer treatment.

Anti-angiogenic-based therapy is one of the standard treatments for mCRC. However, late-line treatment options for refractory mCRC are limited, said Chi.

“Although median OS did not reach significant improvement [in this study], those with RAS/KRAS/BRAF wildtype might be potential patients for anlotinib treatment,” Chi and co-authors concluded. The influence of subsequent therapy on OS will be investigated, Chi added.