Anlotinib Improves PFS in RAS/BRAF Wildtype-Positive Metastatic Colorectal Cancer

Treatment with the multi-target tyrosine kinase inhibitor (TKI) anlotinib (AL3818) led to a significant improvement in progression-free survival (PFS) along with a tolerable and manageable safety profile in Chinese patients with refractory metastatic colorectal cancer (mCRC), according to results from the phase 3 ALTER0703 trial presented during the 2021 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium.

In the mCRC treatment paradigm, anti-angiogenic therapy is considered to be the standard-of-care, however, few options exist for patients in later-line settings. Preliminary data from a cohort of 31 patients suggested that anlotinib monotherapy may be an appropriate option. The agent previously achieved an objective response rate (ORR) of 6.45% (95% CI, 0.8%-21.4%), which include partial responses (PRs) in 6.45% of patients and stable disease (SD) in 83.87% for a disease control rate (DCR) of 90.32% (95% CI, 74.2%-98.0%). The survival data for this early research shows a median PFS of 5.62 months (95% CI, 3.80-7.32), and a median overall survival (OS) of 9.33 months (95% CI, 8.46-10.21).

To further explore the anti-tumor efficacy of anlotinib as well as the safety of the agent, the ALTER0703 study involved administration of the drug in third-line setting of mCRC and beyond in patients who received 2 or more prior lines of chemotherapy. The population was 18 years of age or older and all patients enrolled had an ECOG performance score of 0 or 1, adequate bone marrow, renal, and liver function.

In a 2:1 randomization, 282 patients in the study were given anlotinib 12 mg daily every 3 weeks in combination with best supportive care (BSC). The other 137 patients enrolled were given a matching placebo in combination with BSC. Treatment was continued until disease progression or intolerable toxicity.

The primary end point explored in the study was OS, and the secondary end points included PFS, ORR, DCR, safety, and quality of life (QoL).

In the anlotinib arm, the median age determined at baseline was 57.5 years (range, 49.0-64.0) with 75.5% of patients being below 65 years of age, notably. In comparison, the placebo arm had a median age of 55.0 years (range, 48.0-63.0) with 81.0% being under the age of 65 years. Most patients in the study were male including 62.8% of the experimental arm and 66.4% of the control arm. Fewer patients in the anlotinib arm had an ECOG performance status of 1 (69.9%) compared with the placebo arm (76.6%). The primary site of disease in the anlotinib arm versus the placebo as determined at baseline was the colon for 50.4% versus 40.2%, the rectum for 45.7% versus 56.9%, and both for 3.9% versus 2.9%, respectively. RAS or BRAF status observed at baseline was wildtype for 36.5% of the anlotinib arm versus 33.6% for the placebo arm, mutant for 45.4% versus 41.6%, and unknown for 18.1% compared with 24.8%, respectively.

Liver metastasis was observed at baseline in 76.6% of patients in anlotinib arm compared with 70.1% in the placebo arm. The time from diagnosis to metastases was less than 18 months for 83.7% of the anlotinib arm versus 82.5% of the placebo arm but was 18 months or more for 16.3% versus 17.5%, respectively.

In terms of prior treatment, 30.5% of the anlotinib reported that they had received prior anti-VEGF therapy, compared with 31.4% of the placebo arm. Eighty-nine percent of the anlotinib arm reported undergoing prior surgery versus 88.3% of the placebo arm. Finally, 35.5% of the anlotinib group reported that they had prior radiotherapy compared with 39.4% of the placebo arm.

Assessment of the primary end point showed that the median OS did not meet the requirements for significance. However, treatment with anlotinib yielded a longer median OS of 8.57 months (95% CI, 7.82-9.72) versus 7.16 months (95% CI, 6.24-8.80) in the placebo arm (HR, 1.02; 95% CI, 0.82-1.27; P = .87). A subgroup analysis of OS revealed an OS benefit with anlotinib among patients with RAS/BRAF wild-type disease. The median OS observed with anlotinib in this subgroup was 11.0 months (95% CI, 8.6-14.1) compared with only 6.7 months (95% CI, 3.5-11.1) among patients given placebo.

Secondary end point survival assessment showed a median PFS of 4.14 months (95% CI, 3.38-4.50) with anlotinib versus 1.45 months (95% CI, 1.41-1.51) in the placebo arm (HR, 0.34; 95% CI, 0.27-0.43; P <.0001).

In terms of responses to therapy, anlotinib led to an ORR of 4.26% (95% CI, 2.2-7.3%) with PRs in 4.26%, SD in 71.63%, and progressive disease (PD) in 16.67%. Notably, 7.45% of the anlotinib group was not evaluable for response. Overall, the DCR in the experimental arm was 75.9% (95% CI, 70.5%-80.8%). In comparison, the placebo arm had an ORR of only 0.73% (95% CI, 0-4.0%). The odds ratio (OR) for the difference in ORR between the anlotinib and placebo arms was 0.165 (95% CI, 0.021-1.286; P =.069). There was 1 PR in the placebo arm while the remaining patients achieved only SD (29.92%) or had PD (53.28%). Response data was not evaluable for 16.06% of the placebo group. Compared with the anlotinib arm, the DCR control rate among patients who received placebo was 30.7% (95% CI, 23.1%-39.1%) showing a significant difference (OR, 0.140; 95% CI, 0.089-0.221; P <.0001).

None of the adverse events (AEs) observed in the study were unexpected according to investigators led by Yihebali Chi, MD, PhD, of the Cancer Hospital at the Chinese Academy of Medical Sciences and Peking Union Medical College. AEs occurred in 99.7% of the anlotinib arm and 95.6% of the placebo arm. In addition, grade 3 or higher AEs occurred in 66.7% of patients who received anlotinib versus 35.8% of those given placebo. Treatment-related AEs occurred in 97.5% of the anlotinib population compared with 86.1% of the placebo population, and these treatment-related AEs were grade 3 or higher for 52.5% of patients versus 19.7%, respectively. Also, treatment-related serious AEs occurred in 12.4% of the anlotinib arm versus 7.3% of the placebo arm.

Hypertension was the most common AE observed. Pneumothorax was the most common treatment-related serious AE, which occurred in 4 patients in total.

The results from ALTER0703 suggest that patients with RAS or BRAF wildtype mCRC may experience longer survival outcomes on treatment with anlotinib, although further research is needed to confirm the potential of anlotinib in this patient population.

_References:

_{Chi Y, Shu V, Ba Y, et al. The efficacy and safety of anlotinib in refractory colorectal cancer: A double-blinded, placebo controlled, randomized phase III ALTER0703 trial. Presented at: 2021 ASCO Gastrointestinal Cancers Symposium; January 15–17, 2021; virtual. Abstract 65.}