Comparing the efficacy of regorafenib and 5-fluorouracil-based rechallenge chemotherapy in the third-line treatment of metastatic colorectal cancer

Colorectal cancer (CRC) contributes highly to cancer-mortality [1]. De novo metastatic patients compose one fourth of CRC patients where 25–30% of patients with early-stage or locally advanced disease become metastatic within 5 years [2]. The 5-year survival is only 6% [3]. Fluoropyrimidine-based treatments either with oxaliplatin or irinotecan formed the backbone of metastatic CRC (mCRC) for decades [4, 5]. Introduction of targeted therapies to backbone treatment prolonged the overall survival (OS) up to 30 months [6, 7]. Yet, disease progression is inevitable. Once the tumor cells develop resistance to two main cytotoxic drugs used consecutively, the remaining options are very few [8].

The recommended third-line treatments for mCRC are either a multi-targeted tyrosine kinase inhibitor, regorafenib, or oral nucleoside analogue, trifluridine/tipiracil (TAS-102) [8]. While these agents brought an alternative to best supportive care, which was the optimal treatment before, they yield minimal response rate and short progression free survival (PFS) (1.9 months for regorafenib (HR 0.49) and 2 months for trifluridine/tipiracil (HR 0.48)) and OS (6.4 months for regorafenib (HR 0.77) and 7.1 months for trifluridine/tipiracil (HR 0.68) [9, 10]. The limited efficacy of these treatments caused the introduction of chemotherapy rechallenge in clinical practice though there is limited data to support this approach [11‐14]. Chemotherapy (CT) rechallenge is reintroduction of the same therapy, after an intervening treatment, to which the tumor developed resistance. There are studies conducted with limited number of patients to assess the efficacy of CT rechallenge [15‐17]. The promising results were gained with rechallenge of oxaliplatin, irinotecan, bevacizumab and cetuximab; however, neither of them compared the rechallenge chemotherapy with the standard third-line treatment [18‐21]. There are only two retrospective studies comparing regorafenib and rechallenge chemotherapy in the third-line which have contradictory results [22, 23]. In this study, we aimed to evaluate the efficacy of regorafenib versus CT rechallenge in the third-line treatment of mCRC.

The most powerful treatment against mCRC is 5-FU based treatments. However, progression after two lines of doublet chemotherapy is unavoidable. Contribution with biological agents has little impact in improvement of OS. In this setting, rechallenge treatment was started to be investigated. Although regorafenib is the standard third-line treatment of mCRC in guidelines, it is still not clear if it is the optimal approach since it was just compared to placebo instead of an active treatment arm [8].

In this study, rechallenge treatment showed better disease control rate and OS compared to regorafenib treatment in third-line. However, the difference in PFS was not statistically significant. The cancer-specific survival data is missing in our study. There was no significant survival difference between patients who received a new biological agent during rechallenge and who received the one they were previously exposed to. So the efficacy of rechallenge treatment can only be attributed to rechallenge chemotherapy. Another possible reason of the lower survival rates seen with regorafenib may be the need for dose reduction related to adverse events. 60% of regorafenib patients required ≥ 50% dose reduction due to intolerance. The decrease in efficacy with inadequate doses of regorafenib is a well-known entity. Regorafenib was also shown to cause more toxicity resulting in discontinuation of treatment. As a result, fourth-line treatment chance is higher with rechallenge treatment. Our study also revealed that chemosensitivity to prior lines of treatment was a major factor in choosing between the treatment options.

The CORRECT and CONCUR trials proved OS improvement with regorafenib against placebo after ≥ 2 or more lines of therapy (1.4 and 2 months, respectively) [9, 24] The PFS and OS with regorafenib treatment in our study (4.01 and 8.08 months, respectively) were comparible with the findings of CONCUR trial (3.2 and 8.8 months, respectively). The higher PFS results in real-world studies can be attributed to the treatment response evaluation intervals (6–8 weeks in CORRECT and CONCUR trial vs 3–4 months in our study group). Main shortcoming of CONCUR and CORRECT trials were comparing regorafenib with placebo instead of active-control. The PFS benefit is probably attributable to the ineffectiveness of control group. Most of the mCRC patients has performance score of 0–1 even after the second-line of treatment and are eligible for systemic treatments. Therefore, placebo would be an under-treatment for this population.

Before the approval of regorafenib in mCRC treatment, few studies questioned the role of chemotherapy rechallenge in third-line. In an explanatory study, promising OS benefit was seen with oxaliplatin rechallenge therapy in patients who had received previous oxaliplatin and irinotecan therapy [25]. The rechallenge therapies assessing the efficacy of irinotecan also reported survival benefit with median OS of 6 and 7.3 months [19, 26]. The limitation of these studies was not using 5-FU as the backbone treatment in the rechallenge. In our study, 95% of the patients in the rechallenge arm received 5-FU based chemotherapy. Although it is not a valid approach to do indirect comparisons, OS rates are better in the literature when irinotecan or oxaliplatin are used in combination with 5-FU derivatives rather than used as a single agent. Our study supports using 5FU based regimens in later lines of treatment.

The effect of rechallenge is well documented but not compared to standardized third-line treatment before 2019. There are three retrospective trials in the literature with controversial results comparing the efficacy of regorafenib with chemotherapy rechallenge in the third-line setting [22, 23]. The PROSERpINA study [17] (n = 341), although underpowered and retrospective, showed the survival benefit of rechallenge against regorafenib and TAS-102 in small number of patients. Ergun et al. [22] (n = 61) couldn’t find any significant difference between rechallenge and regorafenib treatment in the third-line setting of mCRC in terms of OS and PFS, nevertheless, recommended rechallenge as an alternative treatment option to regorafenib in progressive disease. They showed a better trend for survival with chemotherapy rechallenge if time to rechallenge was more than 6 months, but this also did not reach statistical significance. Kostek et al. [23] (n = 104), on the other hand, revealed that rechallenge is more effective than regorafenib in terms of PFS and OS, especially in patients with partial response or stable disease after first- and second-line therapies. These studies constitute the most similar design with rechallenge arm of our study however the main disadvantage of these studies is small sample size which should be cautiously interpreted. The full-text of PROSERpINA study has not been published so we cannot reach the details to make comparisons. Our study had similar characteristic in terms of ethnicity, mean age and performance status compared to other retrospective series. Our study reports the highest number of patients in literature comparing the two treatments and having OS benefit. One of the most likely explanations of OS benefit is the possibility of access to more lines of treatment after rechallenge therapy, whereas most of the patients are not eligible for further treatment after regorafenib treatment. The ongoing randomized FIRE-4 trial [27] is the first prospective trial seeking the answer of rechallenge vs regorafenib in mCRC in the third-line setting. While waiting for the results of FIRE-4 trial, considering the lack of proactive data, the rechallenge therapy is another alternative treatment in the third-line treatment of mCRC.

The adverse events seen with rechallenge and regorafenib may change the course of treatment. In 81 patients, regorafenib dose was reduced by ≥ 50% and this reduction was related to worse survival (6.05 vs 11.21 months, respectively). In a study done by Dane et al. [28], regorafenib related toxicities led to treatment discontinuation in 17% of patients which is compatible with the literature. The most common side effect of chemotherapy rechallenge was neuropathy which may sometimes be handled just with palliative treatment or dose reduction. The poorly tolerated treatments may cause non-compliance, decrease efficacy and cause these patients to lose their opportunity to continue with fourth-line of treatment.

After the introduction of rechallenge in 2015 for the first time, ESMO guidelines mentioned the possibility of reintroducing the same therapy that the tumor has already been exposed to [29]. The mechanism underneath the success of chemotherapy rechallenge is still a question mark. It can be explained by the cellular heterogeneity of the cancer [30]. Tumor harbors cells that are resistant and sensitive to the treatment at the same time. Second line therapies may sensitize patients to the previous therapies by promoting the growth of sensitive clones to first line treatment or epigenetic changes may result in reversable tumor resistance after drug holiday [31].

The major limitation of our study is its retrospective nature. The medical records reached from different centers may host bias. One of the most important data on treatment decisions, ECOG PS, is not fully reliable in data-based studies. Another possible limitation that cause lack of PFS benefit might be biased information regarding the timing of disease progression. This can affect the accuracy of PFS measurements. Another one is the unmeasured confounding variables or factors that influence disease progression but are not considered in the analysis. OS, being a more comprehensive endpoint, accounts for a broader range of factors that contribute to overall survival. Nevertheless, our patient population is representative of daily practice and when the efficacy of regorafenib in patients who progressed after multiple lines of therapy is considered, reintroduction of chemotherapy is a good third-line scenario to increase the treatment options in mCRC until randomized studies are designed or prospective studies are concluded.

In the absence of data from prospectively randomized trials, comparing the rechallenge treatment with regorafenib in mCRC, our study contributes valuable data to literature. Higher disease control and OS rates were achieved with rechallenge treatment compared to regorafenib, especially in patients who achieved disease control in one of the first two lines of therapy. Rechallenge treatment should be preferred as a valuable option in patients with mCRC in third-line against approved therapies.