Three Tenets to Prevent Stivarga-Related Side Effects, Improve Survival and Quality of Life

Utilizing a dose escalation strategy, as well as preemptive use of a steroid cream and close follow-up within the first few months of initial treatment with Stivarga (regorafenib) may reduce side effects from the tyrosine kinase inhibitor (TKI) while improving quality of life, according to Dr. Tanios S. Bekaii-Saab.

Stivarga confers an improved survival benefit in patients with refractory metastatic colorectal cancer; however, side effects, like hand-foot skin reaction, may occur within the first two to three weeks after treatment initiation, with the most severe events occurring after week three or four. These common toxicities can be expected with oral TKIs, like Nexavar (sorafenib), but most of the toxicities tend to come a little bit later with those agents, Bekaii-Saab explained.

“The (idea) is, as you're starting the patient on treatment, those that are able to continue through it will see the benefits. Unfortunately, because of the early toxicities, a lot of patients end up stopping treatment prematurely, understandably so,” he added.

Hand-foot skin reaction, for example, causes redness, swelling and pain on the palms of the hands and/or the soles of the feet, which could limit walking or the use of one’s hands. “You can imagine that's incredibly disruptive,” said Bekaii-Saab, medical oncologist, leader of the Gastrointestinal Cancer Program at the Mayo Clinic Cancer Center, medical director of the Cancer Clinical Research Office and vice chair and section chief for medical oncology in the Department of Internal Medicine at the Mayo Clinic in Phoenix.

Therefore, he and his colleagues felt there was a need to determine ways to negate these toxicities so patients could stay on treatment with Stivarga in order to maximize the benefit of its improved survival outcomes.

“Most survival reported on this agent and similar agents is about six months, on average. In this case, you double the survival if you're able to get them to cycle three. So, we need strategies that mitigate some of the toxicities that ultimately have the patient stop the drug too prematurely and appear to negatively affect the overall outcome,” Bekaii-Saab said.

In the randomized, multicenter, open-label, phase 2 Regorafenib Dose Optimization Study (ReDOS) trial, the researchers evaluated four groups of patients treated with Stivarga:

• 54 patients were treated with a dose-escalation strategy: a starting dose of 80 mg per day orally, with weekly escalation of 40 mg each week, as tolerated, until a dose of 160 mg per day was reached.
• 62 patients were treated with a standard-dose strategy of 160 mg per day orally for 21 days of a 28-day cycle.
• 61 patients were preemptively treated with 0.05% clobetasol cream twice daily, applied to palms and soles before Stivarga treatment.
• 55 patients were reactively treated with 0.05% clobetasol cream twice daily, applied to palms and soles during Stivarga treatment.

They aimed to determine the proportion of patients who initiated cycle three of treatment.

After a median follow-up of 1.18 years, 23 patients (43%) treated with the dose escalation strategy and 16 patients (26%) treated with the standard dose initiated cycle three of treatment. The most common side effects experienced by those treated in the dose escalation and standard dosing strategies were fatigue (13% versus 18%, respectively), hand-foot skin reaction (15% versus 16%), abdominal pain (17% versus 6%) and hypertension (7% versus 15%). In addition, 14 patients had at least one drug-related serious side effect: six patients in the dose-escalation group and eight patients in the standard-dose group.

“With (dose escalation) by itself, it did not only improve the outcomes, meaning patients were more likely to stay on treatment, they're more likely to benefit from treatment and their survival was increased by an average of four months, at least,” Bekaii-Saab said. “But what we've seen also is a significant cut in toxicities as well as in the likelihood of the patients discontinuing treatment.”

When evaluating the use of clobetasol cream, 30% of those who followed the preemptive use strategy had no evidence of hand-foot skin reaction, compared with 13% who used the cream reactively during the first two cycles of treatment. During the first cycle, 54% and 45% of patients, respectively, had no hand-foot skin reaction, and 33% and 15% did not experience the side effect in the second cycle. During the second cycle, rates of grade 1, 2 and 3 hand-foot skin reaction were 30%, 8% and 3%, respectively, with preemptive clobetasol and 43%, 18% and 7%, respectively, with reactive clobetasol.

Moreover, patient-reported outcomes showed that the side effect compromised nearly all activities of daily living with worse quality of life in patients who received reactive versus preemptive clobetasol.

Bekaii-Saab noted that this finding has changed his practice in treating patients with Stivarga. “For many of my patients, now I do preemptive steroids. Ultimately, I think this is going to become a practice for every single one of our patients that goes on regorafenib,” he said. “We're even using it, based on this data, with other tyrosine kinase inhibitors. So this has expanded beyond regorafenib. This has changed, for all patients I hope, how we bring out some of these toxicities that can be incredibly limiting to quality of life.”

Ultimately, he added, the dose escalation strategy should be the standard of delivering Stivarga to patients, as well as the use of preemptive steroid creams. Lastly, Bekaii-Saab noted the importance of follow-up, in particular with the increased use of telemedicine following the COVID-19 pandemic.

“It has made it much easier for us to check on patients without bringing them to the clinic. The first month, my pharmacist, my nurse, and when possible myself, we get in touch with the patient,” he said, adding that follow-ups are the “third shield that will prevent those patients from going through a worse outcome.”

“They're already suffering from the cancer, we just want to make their lives better, not make it worse. And I think that if we don't do all the right things, we may actually impede their quality of life. If we do all the right things, then their quality of life is preserved and their survival is significantly improved. And they're more likely to get through more lines of therapy, which extends their survival significantly. So it's important. Cream, dose escalation strategy and close follow up are the three tenets of getting those patients through treatment.”