N Arvind Dasari, MD, The University of Texas MD Anderson Cancer Center, Houston, Texas, recaps the results of the phase 3 FRESNO-2 trial, testing the highly selective, oral tyrosine kinase inhibitor of VEGFR-1, -2, and -3 fruquintinib among patients with metastatic colorectal cancer who had received ≥3 lines of prior therapy. In this global clinical trial, fruquintinib demonstrated significant and meaningful improvement in overall survival and tolerability. According to Dr Dasari, these results support fruquintinib as a new treatment option for this patient population.

These results were first presented at the 2022 European Society of Medical Oncology (ESMO) Congress.

Transcript:

Hello, I'm Arvind Dasari. I'm a medical oncologist in the Department of GI Medical Oncology at the University of Texas, MD Anderson Cancer Center. Today I will be discussing the results of FRESCO-2, a global, phase 3, multiregional clinical trial evaluating the efficacy and safety of fruquintinib in patients with refractory metastatic colorectal cancer.

As you're all aware, the VEGF pathway is a key mediator of angiogenesis, which is necessary for tumor growth and metastasis. Fruquintinib is a highly selective and potent oral tyrosine kinase inhibitor of VEGF receptors 1, 2, and 3. This drug was approved in China based on the phase 3 FRESCO study that showed an improvement in the primary end point of overall survival vs placebo with a hazard ratio of 0.65 and improvement in progression-free survival with a hazard ratio of 0.26.

However, there were significant differences in the standard of care in China at the time of conducting this trial compared to the current global practices. For instance, only 30% of the patients received prior anti-VEGF antibody, and none received TAS 102 or regorafenib. Acknowledging these differences from the current global practices and the huge unmet need for effective treatment options in the refractory setting for metastatic colorectal cancer patients, FRESCO-2 was conducted as a global phase 3 study to evaluate the efficacy and safety of fruquintinib in more heavily pretreated patients.

Eligible patients in FRESCO-2 were required to have prior treatment with all standard cytotoxic chemotherapy agents and anti-VEGF antibody and targeted therapies as appropriate. They were also required to have prior TAS 102 and/or regorafenib. These eligible patients were randomized 2-to-1 to fruquintinib versus placebo. Both were dosed as 5 milligrams POQ daily, 3 weeks on, 1 week off, and patients in both arms also received best supportive care. The primary objective of the study was overall survival with progression-free survival being a key secondary end point. Other secondary end points included objective response rate, disease control rate, and safety.

Assuming a median overall survival of 5 months in the placebo arm with improvement by 1.8 months to 6.8 months in the experimental arm corresponding to hazard ratio of 0.73, 687 patients were required to provide 90% power with a 2-sided alpha of 0.05.

Between September 2020 and December 2021, 691 patients were enrolled. The median number of prior cycles of therapy was 5 in these patients, and almost all patients received a prior anti-VEGF antibody. About 90% received prior TAS 102 and about 50% received prior regorafenib.

The study met its primary end point with improvement in overall survival with a hazard ratio of 0.66. That is a 34% reduction in the risk of death. This corresponds to an improvement in median overall survival from 4.8 months in the placebo arm to about 7.4 months in the fruquintinib arm. That is a difference of 2.6 months with a highly significant P-value. There's also significant improvement in the progression-free survival, which as you may recall, is a key secondary endpoint with a hazard ratio of 0.32 with improvement in median PFS from 1.8 months to 3.7 months in the fruquintinib arm, corresponding to a difference of 1.9 months.

The subgroup analysis for both overall survival and progression-free survival should benefit across all subgroups, suggesting this drug would be effective across all tested subgroups.

Disease control rate was also significantly higher in the fruquintinib arm at 56% versus 16% in the placebo arm. Overall, the drug also appears to be well tolerated with the most common grade ≥3 adverse events being hypertension in about 14%, asthenia in about 8%, and decreased appetite in about 2%. Of note, grade ≥3 occurrences of hand-foot syndrome, proteinuria, and liver function test (LFT) changes were all 6% or lower.

So in summary, FRESCO-2 met its primary end point of overall survival with a hazard ratio of 0.66. There was also improvement in the key secondary end point of progression-free survival with a hazard ratio of 0.32. These are both clinically and statistically significant and consistent across all pre-specified subgroups. Fruquintinib was also well tolerated and consistent with prior established monotherapy profile.

Overall, these results validate those noted by FRESCO and support a new global treatment option for metastatic colorectal cancer patients, enriching the treatment continuum for these patients. Thank you very much.

Source:

Dasari NA, Lonardi S, Garcia-Carbonero R, et al. “LBA25 – FRESCO-2: A global phase III multiregional clinical trial (MRCT) evaluating the efficacy and safety of fruquintinib in patients with refractory metastatic colorectal cancer.” Presented at European Society for Medical Oncology Congress; September 9-13, 2022; Paris, France.