Optimizing Regorafenib Dosing and Patient Management in Colorectal Cancer in Latin America: Perspectives from Argentina

Short abstract

Colorectal cancer (CRC) is one of the most commonly diagnosed cancers in Central and South America and one of the top causes of cancer death; however, these rates vary considerably between countries. This commentary focuses on clinical experiences in Argentina, highlighting results of the phase II ReDOS trial.

Colorectal cancer (CRC) is one of the six most commonly diagnosed cancers in Central and South America, with an incidence rate of 11.0 and 18.6 per 100,000 population, respectively, and one of the top six causes of cancer death, with a mortality rate of 5.3 and 8.9 per 100,000 population, respectively; however, these rates vary considerably between countries [1, 2]. Notably, incidence and mortality rates associated with CRC are increasing in Central and South America [2].

For patients with metastatic CRC (mCRC) whose disease progresses after all standard therapies, regorafenib, an oral multikinase inhibitor [3], is a Food and Drug Administration‐ and European Medicines Agency–approved treatment option that is recommended in the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines [4, 5, 6, 7]. Regorafenib was first approved (based on a conditional recommendation) in Argentina in July 2013 [8], then Mexico in October 2014 [9], followed by Brazil in October 2018 [10]; at the time of writing, approval is pending in Colombia. Approval of regorafenib was based on the results of the international, phase III, randomized CORRECT trial involving 760 patients from 114 centers in 16 countries across North America, Europe, Asia, and Australia [11]. In CORRECT, regorafenib improved overall survival (OS) versus placebo in patients with treatment‐refractory mCRC (median OS: 6.4 vs. 5.0 months, respectively; hazard ratio [HR] 0.77; 95% confidence interval [CI] 0.64–0.94; one‐sided p = .0052) [11]. The survival benefit with regorafenib was confirmed in Asian patients with treatment‐refractory mCRC in the randomized, phase III CONCUR trial (median OS: 8.8 vs. 6.3 months, respectively; HR 0.55; 95% CI 0.40–0.77; one‐sided p = .00016) [12]. In both trials, patients received the currently approved dose of regorafenib (160 mg once daily) or matching placebo for the first 3 weeks of each 4‐week cycle [4, 5, 11, 12].

The most frequent drug‐related all‐grade adverse events (AEs; >25% of patients) in the CORRECT study included hand–foot skin reaction (HFSR), fatigue, diarrhea, anorexia, hypertension, oral mucositis, and rash/desquamation, most of which occurred early during regorafenib treatment (Cycles 1–2) [11]. Grade 3 regorafenib‐related HFSR was reported in >15% of patients in the CORRECT and CONCUR trials [11, 12] and frequently required management with dose modifications (reductions or interruptions; 67% of regorafenib‐treated patients in CORRECT and 71% in CONCUR) [11, 12]. Based on this consistent toxicity profile, some institutions have started to adopt flexible dose optimization strategies to reduce the need for dose modifications and to ensure patients remain on treatment through the early treatment period when most AEs occur. These strategies involve initiating regorafenib at lower doses (80 mg/day or 120 mg/day) than the approved dose (160 mg/day), followed by dose escalation based on tolerability [13]. However, until recently, evidence from prospective studies on the effects of different dosing strategies on the efficacy and safety of regorafenib were lacking.

Regorafenib Dose‐Optimization Strategies

Recently, several prospective studies have reported real‐world clinical use of regorafenib in patients with mCRC, in which a substantial proportion of patients have initiated regorafenib at doses lower than the approved 160 mg/day. In the prospective, observational CORRELATE study, conducted in several regions including Latin America, Europe, and Asia, almost half (43%) of the 1,037 patients commenced treatment below the recommended dose, predominantly at 120 mg/day [14]. Despite the reduced starting dose, the median OS (7.7 months) and median progression‐free survival (PFS; 2.9 months) were consistent with those reported in CORRECT and CONCUR [11, 12, 14]. In the 21 patients from Latin America (Argentina and Mexico) who participated in CORRELATE, 62% of patients started regorafenib at <160 mg/day and 52% of all patients had dose modifications [15]. In a recently published small case series in Chile, 13 patients initially received regorafenib 80 mg/day, which was increased after 2 weeks to 120 mg/day if tolerated [16]. The median OS and PFS were also consistent with findings from prior randomized trials (8.6 and 2.2 months, respectively). Similar clinical benefit has been reported with regard to flexible regorafenib dosing in patients with mCRC in other regions (e.g., in the phase II REGOCC study involving 60 Japanese patients who commenced regorafenib at 120 mg/day) [17].

Although these studies suggest that starting regorafenib at a lower‐than‐approved dose may not compromise efficacy, evidence from prospective, randomized studies has only recently been published. The randomized, phase II ReDOS trial conducted in the U.S. showed that patients with treatment‐refractory mCRC can benefit from a weekly dose escalation of regorafenib from 80 mg/day to 160 mg/day, depending on tolerability [18]. In this trial, 123 patients were randomized (1:1) to receive either regorafenib 80 mg/day, with weekly dose escalation to 160 mg/day (in the absence of disease progression and significant drug‐related toxicities), or the standard 160 mg/day for the first cycle of therapy, both in a 3 weeks on/1 week off schedule. In Cycle 2 and all subsequent cycles, patients received the highest tolerated dose from Cycle 1. Significantly more patients receiving the escalating dose versus the standard dose completed two cycles of regorafenib and started Cycle 3 (43% vs. 26%, respectively; p = .043). There was also a numerical, but not statistically significant, improvement in OS in the dose escalation arm compared with the standard dose (median OS: 9.8 vs. 6.0 months, respectively; HR 0.72; 95% CI 0.47–1.10; p = .12). The severity of some AEs was slightly lower during Cycles 1 and 2, and patient quality of life at Week 2 improved in the dose escalation arm compared with the standard dose arm [18]. As a result of the ReDOS data, the NCCN treatment guidelines for colon and rectal cancers have been updated to include the first‐cycle dose escalation regimen (80 mg/day Week 1, 120 mg/day Week 2, 160 mg/day Week 3, followed by 160 mg/day from Cycle 2 onward) [6, 7]. Recent results from the randomized, phase II REARRANGE study provide additional support to first‐cycle flexible dosing by demonstrating numerical improvements in relevant AEs including fatigue, HFSR, and hypertension without negatively impacting efficacy with a lower starting dose of 120 mg/day in Cycle 1 [19]. A single‐arm, phase II, dose escalation study (DEREGULATE) of regorafenib (80 mg/day starting dose with escalation considered every 2 weeks during the course of treatment) in Japanese patients with mCRC is ongoing [20]. These findings have the potential to change treatment practice by offering physicians an alternative strategy that may help mitigate toxicities and ensure continued treatment.

Our Experience in Argentina

Prior to the availability of the ReDOS data, we had been using locally formulated flexible dosing strategies to manage patients on regorafenib in our Argentinian centers. Our strategy is similar to the ReDOS strategy in that the patients are started at a lower dose—usually 80 mg/day—and the dose is escalated to a maximum of 160 mg/day depending on tolerability (Fig. 1). The focus of our strategy is flexibility in the early stages of treatment rather than escalation per se to ensure that patients reach their optimal dose. We find that patients with a poorer Eastern Cooperative Oncology Group performance status at baseline are less likely to tolerate dose escalation to the full dose. Although patients with a poorer performance status tend to be older, escalation usually depends on individual AEs rather than baseline characteristics. In our experience, the final dose for most patients is 120 mg/day either because patients were not able to escalate further or because the dose had to be reduced from 160 mg/day owing to toxicity. However, it is worth noting that there are some patients across the centers who have derived long‐term benefit from staying on 80 mg/day. Overall, our institutional experience with flexible dosing is consistent with the findings from ReDOS in that we have found it useful in managing AEs early in the treatment course without negatively impacting efficacy.

Figure 1.

Dosing strategies employed at our institutions in Argentina, in the ReDOS study [18], and in Latin American countries in the real‐world CORRELATE study [14].

As recommended in the regorafenib label, our patients continue to be monitored frequently for regorafenib‐related toxicities, especially severe hepatotoxicity, and the regorafenib dose is modified or discontinued as appropriate [4, 5, 13, 21]. In our experience, asthenia/fatigue is the most common reason for the dose not to be escalated to the full dose, but we have found that these AEs can generally be managed at 120 mg/day. We may also prescribe prophylactic treatment with low‐dose corticosteroids (prednisone or dexamethasone), which, in some cases, could reduce fatigue, provide nonpharmacologic interventions such as psychoeducational support, and encourage regular physical activity [22].

Of note, neither the incidence nor management of HFSR has been problematic in our institutions. This has been achieved through early involvement of a dermatologist who meets with patients prior to and during Week 1 of treatment, provides information regarding expected regorafenib skin toxicities and skin care based on the label [4, 5], and recommends management strategies [21] (Tables 1, 2). Patient support and education is typically a collaborative effort provided by the oncologist and dermatologist. Our oncology nurses manage toxicities but are not involved in patient education.

Table 1.

Protocol for regorafenib‐related HFSR management at our Argentinian institutions

Grade	HFSR management [21, 23]
1	Frequently apply emollients and creams to maintain skin moisture, prevent cracks/breaks, and provide relief
2	Consider adding local topical steroids, such as clobetasol 0.05% ointment, to erythematous areas twice daily Topical analgesics to manage pain
3	More intense topical therapies for symptomatic relief For severe HFSR, a combination of cortisone cream and topical antibiotic

Abbreviation: HFSR, hand–foot skin reaction.

Table 2.

Recommended dose modification and measures for regorafenib‐related grade 3 HFSR at our Argentinian institutions

Skin toxicity, grade	Occurrence of skin toxicity	Recommended dose modifications and measures [4, 5]
3	First	Institute supportive measures immediately. Interrupt therapy for a minimum of 7 days until toxicity resolves to grade 0–1 When restarting treatment, decrease dose by 40 mg (one tablet) Dose re‐escalation is permitted at the discretion of the physician
	Second	Institute supportive measures immediately Interrupt therapy for a minimum of 7 days until toxicity resolves to grade 0–1 When restarting treatment, decrease regorafenib dose by 40 mg (one tablet)
	Third	Permanently discontinue regorafenib treatment

Abbreviation: HFSR, hand–foot skin reaction.

In summary, our clinical experience in Argentina supports a personalized and flexible regorafenib dose escalation strategy that does not appear to compromise efficacy. The findings from the randomized, phase II ReDOS trial confirm the validity of this approach.

Disclosures

Mariano Dioca: Amgen, Bayer, Merck Serono, Novartis, Sevier (C/A), Servier (RF), Bayer, Novartis, Servier (H), Amgen, Bayer, Merck, Merck Sharp & Dohme, Sevier (SAB); Juan Manuel O'Connor: Bayer, Merck Serono, Servier (C/A), Bayer, Bristol‐Myers Squibb (RF), Bayer, Merck Sharp & Dohme, Raffo, Servier (H), Bayer, Merck, Merck Sharp & Dohme, Servier (SAB).

(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board