Sequenced treatment after regorafenib and survival in metastatic colorectal cancer: a qualitative clinical review
Abstract
There is limited evidence-based guidance regarding treatment sequencing and outcomes following regorafenib in patients with refractory metastatic colorectal cancer (mCRC). A targeted literature review was conducted to identify studies with clinical outcomes associated with regorafenib therapy and subsequent treatment following regorafenib therapy. The median overall survival range of the nine studies with sequenced-based survival data was 2.1–19.3 months for regorafenib prior to subsequent therapy in refractory mCRC. Safety outcomes in patients treated with regorafenib prior to other therapies in mCRC were generally comparable to reported adverse events in clinical trials for subsequent agents. Data from this review demonstrate a potential correlation between survival and the use of regorafenib prior to subsequent chemotherapy or targeted therapy in patients with refractory mCRC.
Plain language summary
There is limited information regarding the best order of medications for the treatment of patients with metastatic colorectal cancer (mCRC). Multiple scientific studies were read to find results associated with regorafenib treatment and other medications that may follow regorafenib treatment in mCRC. In these studies, patients lived between 2.1 and 19.3 months when using regorafenib before other medications. Patients treated with regorafenib before other medications had the same side effects as if they were only treated with the other medications. Using regorafenib before other medications may be useful in patients with mCRC.
There is not a defined optimal treatment sequence for metastatic colorectal cancer (mCRC) across multiple lines of therapy.
Real-world analysis was positive for patients receiving postregorafenib treatment.
There was a potential correlation between survival and the use of regorafenib prior to other therapies, including standard of care, in patients with refractory mCRC.
The established safety profile of other therapies used in patients with refractory mCRC was not altered by the use of regorafenib prior to these therapies.
Reintroducing chemotherapy and/or targeted therapies after regorafenib treatment is an option for patients with a good performance status.
Regorafenib earlier in therapy for patient with refractory mCRC may provide additional treatment sequencing options.
Colorectal cancer (CRC) is the fourth most commonly diagnosed cancer and third-leading cause of cancer-related mortality worldwide [1–3]. In the US, an estimated 151,030 new CRC cases will be diagnosed in 2022, with approximately 52,580 deaths attributed to CRC [1,3]. Recent US studies have highlighted a rising incidence of CRC in individuals <50 years of age, with the age-adjusted incidence rates increasing from six per 100,000 persons in 2000 to 8.7 per 100,000 persons in 2019 [4,5]. Advances in early detection screenings and treatment have reduced CRC mortality in high-income nations, as the relative survival from 2012 to 2018 for localized CRC was 90.9%; however, relative survival with metastatic colorectal cancer (mCRC) is only 15.1% [3]. Survival for patients with mCRC has increased since the early 2000s, in part due to treatment options available in later lines of therapy for mCRC.
The standard treatment for patients with mCRC in the first- and second-line setting is generally chemotherapy, often combined with VEGF targeted therapies or, for patients with RAS wild-type status, EGFR targeted therapies [6]. Additionally, patients may receive immunotherapy for mismatched repair deficiency or microsatellite instability-high tumors in the first-line or subsequent setting [6,7]. In patients fit for chemotherapy, other targeted therapies are generally relegated to the second-line or subsequent setting and include therapies targeting HER2 amplification (anti-HER2 therapies), BRAF V600E mutations (BRAF inhibitors with EGFR targeted therapies) and NTRK gene fusions (TRK inhibitors) [6,8–10]. However, nearly all patients progress and require subsequent lines of therapy [11].
In subsequent lines of therapy, treatment historically has consisted of recycling of previously used chemotherapy. However, the majority of the data supporting recycling with chemotherapy or targeted therapies comes from retrospective analyses. A recent Phase II study (CHRONOS) of panitumumab rechallenge guided by monitoring of the mutational status of RAS, BRAF and EGFR in ctDNA in patients with mCRC led to further objective responses in 30% of patients [12]. As the data remain limited, rechallenging with previously used treatments should be reserved for later lines of therapy [13].
Two therapies have approval in the third-line or subsequent setting, lending to additional treatment options for patients with refractory mCRC [14–16]. One such therapy, approved in 2015, is trifluridine/tipiracil (TFTD), a combination of trifluridine, a nucleoside metabolic inhibitor and tipiracil, a thymidine phosphorylase inhibitor. TFTD is indicated for the treatment of adult patients with mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy; an anti-VEGF biological therapy; and if RAS wild-type, an anti-EGFR therapy [16]. Regorafenib, a kinase inhibitor, was approved in 2012 for the treatment of patients with mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy; an anti-VEGF therapy; and if RAS wild-type, an anti-EGFR therapy [15]. A recent systematic literature review concluded that both regorafenib and TFTD are appropriate choices prior to treatment rechallenge due to their efficacy and safety profiles. Treatment rechallenge should be reserved for patients who are willing and able to receive further lines of therapy after regorafenib or TFTD to receive as much benefit as possible [13,17].
Despite the available therapies, there is currently no defined optimal treatment sequence for mCRC across multiple lines of therapy [18,19]. Patients with mCRC move through lines of therapy based on patient- and disease-specific characteristics and tumor biomarker profiles, in addition to patient and physician preference [6,11]. When choosing therapy, consideration must be given to the goals of therapy, the type and timing of prior therapy, the mutational profile of the tumor and the differing toxicity profiles of the various agents [14]. The better patients are managed in the first two lines of therapy, the more likely they will be able to reach the third-line setting and beyond [20].
Although guidelines provide multiple treatment options, even within the third-line and subsequent setting, few insights are provided to guide selection and sequencing of treatment [19]. The choice of regorafenib as compared with TFTD or recycling of previously used chemotherapy in patients treated in the third-line setting for mCRC is not well established [11,19]. However, with survival increasing in mCRC, the goal is now to expose patients to all lines of available therapy that can potentially further prolong survival [14].
A targeted literature review (TLR) was performed to support clinical expert opinion on the use of regorafenib in the treatment sequence of patients with refractory mCRC. The focus for this review was on outcomes related to treatment sequencing of regorafenib given prior to or after additional lines of therapy in patients with refractory mCRC. The database searches were conducted in Medline (via EMBASE) and EMBASE and the criteria for study inclusion in this review were studies in humans available in English with a global focus, published between 1 January 2010 and 6 October 2020; all eligible studies were screened by a single reviewer. Studies included patients who received any treatment given after regorafenib that evaluated overall survival (OS), progression-free survival (PFS) and safety.
Regorafenib in the treatment of mCRC
Regorafenib is a small-molecule inhibitor of multiple kinases (including VEGF receptors, FGF receptors, PDGF receptors, BRAF, KIT and RET) that are involved with various processes including tumor growth and angiogenesis. Regorafenib is dosed at 160 mg orally once a day on days 1–21 and repeated every 28 days [15]. The approval of regorafenib for the treatment of mCRC was based on the CORRECT trial [13]. This trial included 753 patients with mCRC and progression on all approved standard therapies who were randomized to regorafenib or placebo. The median OS for regorafenib treated patients was 6.4 versus 5.0 months for placebo (hazard ratio [HR]: 0.77; 95% CI: 0.64, 0.94; p = 0.0052). The CONCUR trial was conducted in a broader population of Asian patients after the CORRECT trial and included 204 patients with mCRC who had received at least two previous lines of therapy or were unable to tolerate standard treatments [21]. Patients were randomized to regorafenib or placebo and the median OS for regorafenib treated patients was 8.8 versus 6.3 months for placebo (HR: 0.55; 95% CI: 0.40, 0.77; p = 0.00016). Other single-arm, Phase III and real-world observational studies of regorafenib support the efficacy observed in these trials [13,22–24]. The CONSIGN trial was a real-world prospective trial that confirmed the safety profile of regorafenib from Phase III trials and reinforced the appropriate management of adverse events (AEs) [22]. Real-world evidence from the REBECCA observational trial included 654 patients treated with regorafenib who demonstrated a median OS of 5.6 months and the CORRELATE study (N = 1037) of regorafenib treated patients in a real-life clinical practice resulted in a median OS of 7.6 months (95% CI: 7.1, 8.2) [13,23]. In the IMblaze370 Phase III trial, for enrolled patients with mCRC who had received at least two prior lines of therapy, the median OS with regorafenib was 8.51 months, which was no different than atezolizumab plus cobimetinib, with an HR of 1.00 (95% CI: 0.73, 1.38; p = 0.99) [25].
The CONCUR trial resulted in a longer median OS than the previously conducted CORRECT trial, suggesting a longer median OS may be related to patients in CONCUR receiving fewer prior lines of therapy, including less exposure to standard of care biologic agents [13]. Additionally, analysis of the CORRECT trial showed that 26% of patients received a subsequent line of treatment after regorafenib therapy, demonstrating additional therapy may be safely introduced following regorafenib [24]. Therefore, the use of regorafenib prior to additional therapy options for patients with mCRC who have progressed on at least two lines of prior therapy may provide a potential treatment sequencing option.
Review of regorafenib sequencing in mCRC
This was a TLR, methodologically defined as a nonsystematic literature review meant to be an informative approach to a specific research question, designed to review outcomes associated with regorafenib therapy and subsequent treatment following regorafenib therapy. Although a TLR is not as comprehensive as a systematic literature review, the focus here is on key research relevant to the research objective. This approach is used in oncology to in order to obtain an understanding of the issues relevant to the research objective, and to potentially be followed by further research that is identified as a gap in the available literature. For this TLR, the prespecified search terms (Table 1) were used to identify relevant publications. Following the identification of relevant publications, the population, intervention, comparators, outcome and study design (PICOS) criteria were used to define the inclusion/exclusion criteria and determine the studies that met inclusion within this TLR (Table 2). The summary of the literature review process and study attributes included in this TLR are outlined in Table 3. In the 23 studies that met the TLR inclusion criteria, 19 reported on the prevalence of additional lines of therapy after regorafenib treatment (postregorafenib) [24,26–47]. Most of the studies (15 of 23 studies) identified TFTD as the most commonly used postregorafenib treatment. Among the 23 studies included in the TLR, the patient age range was 23–88 years, and 69% of the patients were male. Approximately 76% of patients included in the studies identified for the TLR had been treated with regorafenib prior to additional therapies. The patient characteristics of the included studies are summarized in Table 4. Of the 23 included studies, 18 were retrospective and reported OS or PFS as the primary outcome. Of these 18 studies that provided efficacy outcomes, nine studies reported these outcomes for regorafenib prior to further line(s) of therapy.
| Database | Embase (including MEDLINE) | ||
|---|---|---|---|
| Search filters applied | Humans; English language only | ||
| Date of search | 2 December 2020 | ||
| Search number | Search | Query | n of records found |
| 1 | Metastatic colorectal cancer | ‘Metastatic colorectal cancer’/exp or ‘metastatic colon cancer’/exp or (colon or rectum or rectal or colorectal) NEAR/2 (cancer or carcinoma* or tumor* or tumor*) NEAR/2 metasta*) | 36,329 |
| 2 | Regorafenib | ‘Regorafenib’/exp or regorafenib:ab,ti or STIVARGA:ab,ti | 4145 |
| 3 | Regorafenib for mCRC | #1 and #2 | 1327 |
| 4 | Filters | #3 and (humans)/lim and (english)/lim | 1263 |
| Additional limits: | |||
| 5 | Limit article type and date for conference abstracts | #4 and (‘article’/it or ‘article in press’/it or ‘review’/it or ([conference abstract]/lim and [2019-2020]/py) | 876 |
| 6 | Date filter for full-text publications | #5 and [2010–2020]/py | 876 |
| Population | Patients with mCRC in the US or other geographies (global) |
| Intervention | Postregorafenib treatments (any) |
| Comparators | Any pharmacologic treatment, postregorafenib Studies without comparators (i.e., studies with only one treatment) could also be included (i.e., single-arm trials or real-world studies of one treatment) |
| Outcomes | • Survival (overall, progression-free) – primary outcome of interest • Safety – primary outcome of interest • Economic (e.g., treatment costs) • Humanistic (e.g., patient QoL) |
| Study design | Real-world observational studies (e.g., prospective and retrospective, surveys, cross-sectional studies); RCTs and other interventional studies SLRs and/or meta-analyses (for reference checking) – may be used |
| Literature review process | |
|---|---|
| Articles that met all inclusion criteria | 23 |
| Articles that only reported on the prevalence of regorafenib as prior treatment | 19 |
| Overall study characteristics | |
| Year of publication range: 2015–2020 | |
| Study design Retrospective studies RCTs Prospective studies Cost–effectiveness studies | 18 3 1 1 |
| Reported outcomes Survival (OS or PFS) Safety Economic burden Humanistic burden | 21 8 1 2 |
| Postregorafenib treatments identified TFTD Chemotherapy not specified FOLFOX Nintedanib Cetuximab Capecitabine, 5FU, leucovorin | 15 5 2 1 1 1 |
| Study (year) | Patients who received regorafenib (n) | Age in years (range) | Gender (% male) | Patients postregorafenib | Postregorafenib treatment (%) | Ref. |
|---|---|---|---|---|---|---|
| Adenis (2016) | 654 | 64 (25–91) | NR | 223 | Chemotherapy only: 48 Chemotherapy + targeted therapy: 45 Targeted therapy only: 7 | [26] |
| Arita (2016) | 43 | 63 (38–85) | 56 | 16 | TFTD: 100 | [27] |
| Bertocchi (2017) | 11 | 56 (42–59) | 54.5 | 11 | Chemotherapy: 72.7 Experimental therapy (clinical trial): 27.2 | [24] |
| Cremolini (2018) | 341 | 61 (33–81) | 62 | 121 | TFTD: 100 | [28] |
| Fok (2020) | 14 | 61.2 (42.1–73) | 71.4 | 2 | TFTD: 100 | [29] |
| Gourzoulidis (2019) | NR | NR | NR | NR | Patients treated with FTD/TPI and regorafenib moved onto regorafenib and FTD/TPI, respectively or BSC | [30] |
| Huemer (2020) | 93 | 65 (42–85) | 58 | 31 | TFTD: 100 | [32] |
| Huemer (2019) | 22 | 59 (42–74) | 50 | 18 | TFTD: 67 | [31] |
| Kotani (2016) | 55 | 66 (38–78) | 49.1 | 32 | TFTD: 100 | [33] |
| Martin-Romano (2020) | 29 | 58 (25–88) | 72 | 3 | NR for postregorafenib patients | [34] |
| Masuishi (2017) | 146 | <65: 55% ≥65: 45% | 62 | 79 | TFTD: 56 Other chemotherapy: 44 | [35] |
| Mayer (2015) | 80 | 63 (27–82) | TFTD: 61 Placebo: 62 | TFTD: 91 Placebo: 53 | TFTD: 63 Placebo: 37 | [36] |
| Moriwaki (2020) | 223 | 64 (31–84) | 57 | 144 | Regorafenib: 1 Other chemotherapy: 8 | [37] |
| Nakashima (2020) | 973 | 66 (60–72) | 62 | 973 | TFTD: 100 | [38] |
| Ogata (2020) | 57 | 66 (41–81) | 53 | 38 | Unspecified chemotherapy; FTD/TPI | [39] |
| Shitara (2019) | 101 | Median (quartiles): 68 (62–74) | 61 | 51 | Cetuximab with or without irinotecan: 100 | [40] |
| Sueda (2016) | 23 | 59 (37–83) | 52.2 | 6 | TFTD: 100 | [41] |
| Tai (2020) | 136 | Mean (SD): 65.8 (13.01) | 61.8 | 41 | riFOLFOXIRI: 100 | [42] |
| Takeuchi (2017) | 17 | Mean (range): 64.2 (42–86) | 53 | 12 | Capecitabine: 42 TFTD: 25 5FU/leucovorin: 17 S1 + irinotecan: 8 FOLFOX: 8 | [43] |
| Tanaka (2018) | 20 | 68 (57–78) | 65 | 7 | TFTD: 100 | [44] |
| Unseld (2018) | 49 | Mean (SD): 62 (10) | 69 | 32 | TFTD: 100 | [45] |
| Unseld (2018) | 48 | Mean (SD): 64.2 (8.7) | 71 | 48 | Chemotherapy: 37.5 | [46] |
| Van Cutsem (2018) | 768 | Nintedanib: 62 (22–85) Placebo: 62 (23–83) | Nintedanib: 61.1 Placebo: 57.1 | Nintedanib 36.5% Placebo: 37.7% | Nintedanib: 100 Placebo: 100 | [47] |
The outcomes associated with regorafenib use prior to the use of further therapy or after a previous line of therapy are outlined in Table 5. In the seven studies that reported median OS based on regorafenib being given before or after TFTD, previously used chemotherapy or targeted therapy, the median OS ranged from 9.1 to 19.3 months for regorafenib first, and 6.6 months to 16.9 months for regorafenib after other therapies [27,38,40,42,44,45]. Of these studies, three studies reported significantly longer median OS (p < 0.05) with regorafenib given prior to additional therapy, including TFTD, previously used chemotherapy or targeted therapy [27,40,42]. Two of the seven studies that reported median OS did not include a statistical analysis of the results; however, the median OS with regorafenib was numerically longer when given prior to TFTD as compared with after TFTD in both of these studies [38,44]. However, it should also be noted that two studies reported no statistical difference in median OS when regorafenib was used prior to or after TFTD in patients with refractory mCRC [41,45]. The seven studies that reported median OS based on regorafenib first or after TFTD, previously used chemotherapy or targeted therapy are described in more detail below [27,38,40,42,44,45].
| Study (year) | Study design | Treatment | Median PFS | Median OS | Ref. |
|---|---|---|---|---|---|
| Shitara (2019) REVERCE | RCT | • Regorafenib first: n = 51 • Cetuximab with or without irinotecan first: n = 50 | PFS1† • Regorafenib first: 2.4 months • Cetuximab first: 4.2 months PFS2‡ • Regorafenib first: 5.2 months • Cetuximab first: 1.8 months Total PFS • Regorafenib first: 9.0 months • Cetuximab first: 7.1 months • p = 0.015 | • Regorafenib first: 17.4 months • Cetuximab first: 11.6 months • p = 0.0293 | [40] |
| Tai (2020) | Retrospective study | • Regorafenib first: n = 136 • riFOLFOXIRI first: n = 55 | • Regorafenib first: 3.17 months (95% CI: 2.38, 3.95) • riFOLFOXIRI first: 4.97 months (95% CI: 3.15, 6.79) • p = 0.622 | • Regorafenib first: 13.8 months (95% CI: 9.61, 17.92) • riFOLFOXIRI first: 10.7 months (95% CI: 8.52, 12.88) • p = 0.038 | [42] |
| Sueda (2016) | Retrospective study | • Regorafenib first: n = 6 of 23 in crossover group • TFTD first: n = 8 of 14 in crossover group | • Regorafenib first: 4.7 months (95% CI: 2.13, 14.7) • TFTD first: 3.7 months (95% CI: 0.92, 8.03) | • Regorafenib first: 11.5 months (95% CI: 5.47, NR) • TFTD first: 7.6 months (95% CI: 2.98, 11.5) | [41] |
| Arita (2016) | Retrospective study | • Regorafenib first: n = 16 • TFTD first: n = 6 | • Regorafenib first: 4.6 months • TFTD first: 1.9 months • p = 0.0025 | • Regorafenib first: not reached • TFTD first: 6.6 months • p = 0.10 | [27] |
| Nakashima (2020) | Retrospective study | • Regorafenib first: n = 973 • TFTD first: n = 1028 | PFS not able to be determined due to limitations of the database | • Regorafenib first: 16.4 months (95% CI: 15.1, 17.8) • TFTD first: 16.9 months (95% CI: 15.5, 17.9) • p = 0.68 • Regorafenib alone: 6.4 months (95% CI: 5.9, 7.0) • TFTD alone: 10.2 months (95% CI: 9.5, 10.1) | [38] |
| Bertocchi (2017) | Retrospective study | • Regorafenib first: n = 11 • Chemotherapy first: n = 117 | • Regorafenib first: 1.6+ months (range: 0.5–3.5 months) | • Regorafenib first: 2.1+ months (range: 0.5–10.2 months) | [24] |
| Unseld (2018) | Retrospective study | • Regorafenib first§: n = 68 • TFTD first¶: n = 17 | • Regorafenib first: 3.1 months (IQR: 2.1–4.6 months) • TFTD first: 2.2 months (IQR: 1.6–3.6 months) | • Regorafenib first: 17.7 months • TFTD first: 8.1 months | [45] |
| Tanaka (2018) | Retrospective study | • Regorafenib first: n = 7 • TFTD first: n = 10 | • Regorafenib first: 2.1 months (95% CI: 1.3, 3.6 months) • TFTD first: 3.1 months (95% CI: 1.7, 4.1 months) • p = 0.13 | OS1# • Regorafenib first: 9.1 months (95% CI: 4.1, 13.4 months) • TFTD first: 9.3 months (95% CI: 5.5, 12.3 months) • p = 0.68 OS2†† • Regorafenib second: 7.1 months (95% CI: 5.0, NA months) • TFTD second: 5.3 months (95% CI: 3.0, NA months) • p = 0.67 | [44] |
| Fok (2020) | Retrospective study | • Regorafenib first: n = 2 | • NA | • Regorafenib first: 207 days and 464 days | [29] |
REVERCE was a randomized controlled trial (RCT) evaluating sequential treatment with regorafenib followed by cetuximab/irinotecan or cetuximab/irinotecan followed by regorafenib in patients with KRAS wild-type locally advanced or mCRC following treatment failure with fluoropyrimidines, oxaliplatin and irinotecan [40]. This randomized Phase II study included 101 patients comparing the primary end point of median OS based on the sequencing of therapies. The median OS was significantly longer among patients receiving regorafenib followed by cetuximab/irinotecan (n = 51) compared with the reverse sequence (n = 50) (17.4 vs 11.6 months, respectively; p = 0.0293).
Tai et al. conducted a 2-arm retrospective analysis of 191 Taiwanese patients with mCRC refractory to fluorouracil, irinotecan, oxaliplatin, cetuximab and bevacizumab to compare the late-line treatment sequence of regorafenib and reduced-intensity oxaliplatin, fluorouracil, irinotecan and leucovorin (riFOLFOXIRI) [42]. The primary objective of this study was to compare the median OS based on the sequencing of therapies. In this study, 136 patients received regorafenib followed by riFOLFOXIRI compared with 55 patients who received riFOLFOXIRI followed by regorafenib. Patients who received regorafenib first had a median OS of 13.8 months (95% CI: 9.61, 17.92) compared with 10.7 months (95% CI: 8.52, 12.88) for patients in the riFOLFOXIRI first group (HR: 0.67; p = 0.038); after controlling for other confounding factors, treatment sequencing remained an independent prognostic factor (HR: 0.674; p = 0.038).
The efficacy and safety of regorafenib or TFTD in patients with mCRC refractory to standard therapies were evaluated in a retrospective study [41]. The study consisted of 37 patients comparing the median OS based on crossover treatment. Median OS in the regorafenib first group (n = 6 of 23 in crossover subgroup) versus the TFTD first group (n = 8 of 14 in crossover subgroup) was 11.5 months (95% CI: 5.47 months, not reached) and 7.6 months (95% CI: 2.98, 11.5 months), respectively. The OS benefit for patients who received sequenced treatment was numerically longer in patients who received regorafenib followed by TFTD or vice versa compared with those who only received one line of therapy for refractory mCRC (followed by best supportive care), with reported median OS in regorafenib and TFTD groups of 5.8 months (95% CI: 3.70, 11.7 months) and 6.3 months (95% CI: 3.21, 9.93 months), respectively.
A total of 43 patients were included in a retrospective study comparing OS in patients receiving TFTD in clinical practice for salvage chemotherapy for mCRC [27]. Patients receiving TFTD pretreated with regorafenib were compared with patients receiving oxaliplatin-, fluoropyrimidine- or irinotecan containing chemotherapy prior to TFTD. Cetuximab or panitumumab was administered to all patients with wild-type KRAS status in this group as well. A subgroup analysis demonstrated improved outcomes with the treatment sequence of regorafenib followed by TFTD. The median OS was not reached versus 6.6 months (p = 0.10) in the regorafenib pretreated group and non pretreated group, respectively.
A retrospective, observational study to compare OS included 80 patients with refractory mCRC treated with TFTD or regorafenib [45]. Of the 80 patients included, 68 patients had received regorafenib prior to TFTD (n = 32) or best supportive care (n = 36) and 17 patients had received TFTD prior to regorafenib (n = 1) or best supportive care (n = 16). In this study, TFTD without regorafenib or with subsequent regorafenib therapy (TFTD first) resulted in a median OS of 8.1 months (interquartile range: 6.7, not reached). The OS for the TFTD treated patients who had previously received regorafenib was 17.7 months (interquartile range: 13.9; not reached).
A retrospective cohort study by Nakashima et al. in 2020 reported that the use of regorafenib prior to TFTD showed no difference in survival compared with the opposite sequence [38]. This study assessed the median OS of regorafenib versus TFTD evaluated in third-line and beyond unresectable mCRC. A subgroup analysis was included that compared the effectiveness between the group in which regorafenib was administered first (n = 973) and the group in which TFTD was administered first (n = 1028). This subgroup analysis, using data over 6 years, demonstrated a slightly lower, although nonsignificant, median OS in the group who was administered regorafenib first versus the TFTD first group (16.4 vs 16.9 months, respectively; adjusted HR: 0.95; p = 0.68).
A retrospective cohort analysis of the multicenter observational study (REGOTAS) assessed the median OS of regorafenib and TFTD in 44 patients with refractory mCRC [44]. Of these 44 patients, 17 patients received therapy with either regorafenib first followed by TFTD (n = 7), or TFTD first followed by regorafenib (n = 10). The median OS was not statistically significantly different from the time of start of treatment for regorafenib first (9.1 months [95% CI: 4.1, 13.4]) as compared with TFTD first (9.3 months [95% CI: 5.5, 12.3]) (p = 0.68).
Of the nine studies included in this TLR, only two studies provided a safety analysis with regard to the administration of regorafenib prior to or after further lines of therapy in patients with refractory mCRC [40,44]. In the REVERCE Phase II RCT, grade 3–4 nonhematologic AEs occurred in 71% of patients who received regorafenib first; 50% of patients who received cetuximab ± irinotecan first; 57% of patients who received cetuximab ± irinotecan after regorafenib; and 63% of patients who received regorafenib after cetuximab ± irinotecan [40]. In this trial, there were also similar rates of hematologic grade 3–4 AEs between arms, which occurred in 14% of patients who received regorafenib first; 16% of patients who received cetuximab ± irinotecan first; 11% of patients who received cetuximab ± irinotecan after regorafenib; and 5% of patients who received regorafenib after cetuximab ± irinotecan [40]. Additionally, in a retrospective study by Tanaka et al. published in 2018, treatment related AEs occurred in 20 (100%) patients for who received regorafenib first and in 22 (92%) patients who received TFTD first [44]. Following crossover between the two therapies, treatment related AEs occurred in eight (80%) patients who received regorafenib after TFTD and seven (100%) patients who received TFTD after regorafenib [44]. The frequencies of grade 3 or 4 leukopenia, neutropenia, anemia and nausea for the use of TFTD after regorafenib were generally comparable with those for the use of TFTD prior to regorafenib (57 vs 29%, 29 vs 34%, 57 vs 38%, 0 vs 8%, respectively) [44]. Similarly, the frequencies of grade 3 or 4 hand-foot skin reaction, increased aspartate transaminase, increased alanine transaminase, and increased bilirubin for regorafenib after TFTD were not greater than the frequencies for the use of regorafenib prior to TFTD (10 vs 45%, 0 vs 5%, 0 vs 5%, 0 vs 10%, respectively) [44]. In both the study by Tanaka and colleagues and in the REVERCE trial, the rates of AEs for TFTD and cetuximab ± irinotecan when given after regorafenib were similar to the AEs reported in the study arm in which these therapies were given prior to regorafenib [40,44]. Evidence from these studies support the safety of regorafenib given prior to further lines of therapy in refractory mCRC [40,44]. Safety outcomes measured in patients treated with regorafenib sequenced before other treatment options in refractory mCRC were generally comparable to reported AEs in clinical trials for the subsequent agents [16,40,44,48].
Discussion
Regorafenib prolonged survival in heavily pretreated patients in RCTs [13,15,16,49], whereas previously used chemotherapy regimens currently have less data to support their use in this setting [11]. Clinical evidence suggests that regorafenib works better in patients with good PS and therefore it should be incorporated into the management of mCRC before patients become too frail and begin to experience a rapid decrease in PS [11].
Evidence from this TLR suggests that regorafenib prior to TFTD, previously used chemotherapy or targeted therapies may provide a treatment strategy that has a potential correlation to survival in refractory mCRC patients, while maintaining the well-established safety profile of these treatments [27,40–42]. Of the seven studies that report median OS with regorafenib first as compared with given after other therapies in refractory mCRC, five studies report either a statistically significantly longer or numerically longer median OS when regorafenib was given prior to TFTD, previously used chemotherapy or targeted therapies [27,38,40–42,44,45]. In the only RCT included in this TLR, the REVERCE Phase II trial, the results suggested that earlier use of regorafenib may improve the survival [40]; however, these results have yet to be proven in a larger study.
The rationale for regorafenib use prior to other therapies in refractory mCRC is that regorafenib may theoretically have a chemosensitizing effect. As CRC is a complex disease involving dysregulation in a number of signal transduction pathways, treatment resistance might be driven by epigenetic changes that occur during treatment within these pathways [50]. Heterogeneity of individual tumor molecular profiles can occur, as the development of subclones that are genetically different following chemotherapy administration has been reported [50,51]. Multikinase inhibition with regorafenib may allow the tumor to revert to previous epigenetic profile or facilitate the re-emergence of chemotherapy- or targeted therapy sensitive tumors [51]. It has been demonstrated that VEGF targeted therapy could enhance sensitivity to both chemotherapy and radiotherapy [50,52]. As such, the mechanism of action of regorafenib may support its use prior to additional chemotherapy due to a potential resensitizing effect on tumors that have previously failed to respond to chemotherapy, leaving patients open for rechallenge of treatments after regorafenib [43,51,53]. The possibility that regorafenib could act as a chemotherapy resensitizing agent must be confirmed by randomized clinical trials [24].
Although safety data were largely unavailable as part of this TLR, the safety data that was available included the administration of therapy, including TFTD or targeted therapy ± chemotherapy, following regorafenib in patients with refractory mCRC [40,44]. When reviewing data from the two studies that published safety data, there did not appear to be a correlation between regorafenib use prior to further therapy and increased toxicity; the safety profiles of these agents when given after regorafenib were largely unchanged from when these agents were given prior to regorafenib in these studies [40,44]. However, the safety and patient tolerability of regorafenib has been a concern among oncologists, and could possibly lead to decreased use prior to other therapies in refractory mCRC.
Although regorafenib has been shown in multiple studies to improve survival in patients with refractory mCRC, the AE profile can limit its use [54,55]. However, using a dose-optimizing strategy for regorafenib may lower the incidence of AEs [49,54]. Two studies have been undertaken to optimize the dosing of regorafenib for patient tolerability. The largest study exploring dosing flexibility for regorafenib was the REARRANGE trial [56]. Although REARRANGE did not meet its primary end point of improving global tolerability of regorafenib with alternative dosing, it demonstrated improvement in fatigue and hypertension without jeopardizing efficacy with these alternative strategies [56]. Additionally, ReDOS was a randomized, multicenter, open-label, Phase II study that evaluated the safety and activity of regorafenib started at 80 mg/day and escalated weekly in 40 mg increments up to 160 mg/day or the standard dose of 160 mg/day for 21 days of a 28-day cycle [55]. Based on this trial, patients in the dose escalation group had a lower incidence of AEs and comparable clinical efficacy, highlighting that alternative dosing strategies could represent an alternative approach to regorafenib use in clinical practice, potentially allowing for use prior to additional therapies in refractory mCRC [55].
Conclusion
Nearly all mCRC patients progress on treatment and require later lines of therapy. Currently, there is not a defined optimal treatment sequence for mCRC across multiple lines of therapy. The use of regorafenib as early as possible in patients who are refractory to standard chemotherapy and targeted therapies, such as fluoropyrimidines, oxaliplatin, irinotecan, anti-VEGF therapy and, if RAS wild-type, anti-EGFR therapy, offers an additional treatment option for mCRC. Regorafenib has been shown to be safe and effective as third-line treatment after standard treatments in mCRC. This review also raises the possibility that regorafenib treatment prior to subsequent treatment with TFTD or rechallenge with standard chemotherapy or targeted therapies may be correlated to prolonged survival in patients with mCRC. Additionally, AEs were not significantly different from the established safety profiles of the chemotherapies or targeted therapies in patients who received regorafenib therapy prior to subsequent treatments. Reintroducing chemotherapy and/or targeted therapies after regorafenib treatment is an option for patients with a good PS who want to continue treatment to maximize the treatment benefit. As the data from this review was derived mostly from small, retrospective analyses, prospective data are needed to determine the optimal treatment sequence in patients with refractory mCRC.
Future perspective
As patient survival is increasing in patients with mCRC, largely due to the availability of multiple effective lines of therapy, a clear treatment strategy is required for the large proportion of patients who receive third or subsequent lines of therapy to ensure maximum benefit and sustained quality of life. Real-world analyses can potentially inform treatment decision-making in the absence of prospective trials. Regorafenib has the potential to improve survival and have no discernable effect on the toxicity of subsequent TFTD, previously used chemotherapy or targeted therapy per the data analyzed in this review. However, treatment of patients with mCRC in the third-line or subsequent setting is likely to become more complicated for practitioners given the many therapies currently in the pipeline. As such, real-world analyses, in the absence of prospective RCTs, may provide data in the evolving treatment landscape of mCRC.
Author contributions
S Babajanyan: conceptualization, methodology; writing – review & editing, supervision; M Pollack: validation, writing – original draft, visualization; S Castelo: validation, writing – original draft, visualization; A Kavati: conceptualization, methodology, validation, resources, writing – review & editing, project administration, funding acquisition; TS Bekaii-Saab: validation, writing – review & editing, supervision.
Acknowledgments
Bayer Healthcare Pharmaceuticals, Inc. provided financial support preparation of the manuscript, which was conducted by Xcenda; the study sponsors were instrumental in the study design and interpretation of the data and the decision to submit the article for publication.
Financial & competing interests disclosure
Bayer Healthcare Pharmaceuticals, Inc. provided financial support for conduct of the targeted literature review and the preparation of the manuscript. The study was wholly conducted by Xcenda, and the study sponsors were instrumental in the study design and interpretation of the data and the decision to submit the article for publication. S Babajanyan is an employee of Bayer Healthcare Pharmaceuticals, Inc. S Castelo and M Pollack are employees of Xcenda, LLC. A Kavati was an employee of Bayer Healthcare Pharmaceuticals, Inc. at the time of study conduct and holds stock in Novartis. TS Bekaii-Saab reports the following potential conflicts of interest: receipt of research funding to his institution from the following companies: Agios, Arys, Arcus, Atreca, Boston Biomedical, Bayer, Eisai, Celgene, Lilly, Ipsen, Clovis, Seattle Genetics, Genentech, Novartis, Mirati, Merus, Abgenomics, Incyte, Pfizer, BMS. Consulting funding to his institution from the following companies: Ipsen, Arcus, Pfizer, Seattle Genetics, Bayer, Genentech, Incyte, Eisai and Merck. Consulting funding to self from the following companies: Stemline, AbbVie, Boehringer Ingelheim, Janssen, Daichii Sankyo, Natera, TreosBio, Celularity, Exact Science, Sobi, Beigene, Kanaph, Astra Zeneca, Deciphera, MJH Life Sciences, Aptitude Health, Illumina and Foundation Medicine. IDMC/DSMB: Fibrogen, Suzhou Kintor, Astra Zeneca, Exelixis, Merck/Eisai, PanCan and 1Globe. Scientific Advisory Board: Imugene, Immuneering, Xilis, Replimune Artiva and Sun Biopharma. Royalties: uptodate. Inventions/patents: WO/2018/183488: Human PD1 peptide vaccines and uses thereof – licensed to Imugene WO/2019/055687: methods and compositions for the treatment of cancer cachexia – licensed to Recursion. The authors would like to acknowledge the medical writing assistance of Brett Maiese and the editorial assistance of Kylie Matthews, both of Xcenda, LLC at the time the manuscript was written. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Ethical conduct of research
The authors state the information drawn from this review were taken from literature that has been previously published.
Open access
This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/
Papers of special note have been highlighted as: • of interest; •• of considerable interest
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