Maintenance strategies in first-line treatment for RAS/BRAF wild-type metastatic colorectal cancer—one size does not fit all

Colorectal cancer (CRC) is the third most prevalent cancer worldwide with close to 1.9 million new patients diagnosed every year (1). In almost half of these patients, metastatic CRC (mCRC) will be detected; either synchronous mCRC when metastases are present at the time of the primary diagnosis or metachronous disease when relapse occurs after curative intended treatment. Nearly 50% of CRC patients die each year.

Currently, first-line chemotherapy consists of a combination of 5-fluorouracil (5-FU) and irinotecan followed by 5-FU and oxaliplatin upon progression (or vice versa); depending on the RAS, BRAF, and mismatch repair (MMR) status, targeted agents are frequently added. An anti-angiogenic drug (e.g., bevacizumab) is often used in patients independently of the molecular subtypes, whereas epidermal growth factor receptor inhibitors (EGFRi) as cetuximab or panitumumab are designated for selected patients whose tumors are RAS and BRAF wild-type (2,3).

RAS (both KRAS and NRAS) and BRAF wild-type mCRC represents a distinct subtype of CRC concerning both prognosis and therapeutic options manifesting in a median overall survival (OS) of about 36 months for selected fit patients included in clinical trials. According to current guidelines, the EGFRi combined with a 5-FU-based doublet [5-FU, leucovorin, and irinotecan (FOLFIRI)/5-FU, leucovorin, and oxaliplatin (FOLFOX)] are the cornerstones of systemic treatment (2,3). This combination frequently results in remarkable response rates and tumor shrinkage, making metastasectomy, e.g., liver resection and/or a local ablative approach feasible even in initially unresectable metastatic cases, improving OS. The OS benefit of first-line EGFRi treatment is limited to patients with left-sided primary tumors; patients with right-sided tumors might also achieve significant response, however, without OS benefit (2,3).

In patients with incurable diseases, where the aim is to relief symptoms and prolong life, balancing efficacy and quality of life (QoL) is paramount. During the continuum of care, keeping toxicities at an acceptable level is crucial for the patients. Induction therapy with doublet chemotherapy and an EGFRi typically lasts 4–6 months resulting in cytoreduction/tumor shrinkage in most cases; the optimal duration of first-line induction treatment is though unknown yet. Considering the EGFRi, skin and gastrointestinal toxicities are the most prevalent, and patients often need treatment breaks despite the comprehensive supportive care provided. The use of an oxaliplatin containing chemotherapy backbone (most often FOLFOX) causes potentially disabling cumulative neurotoxicity, leading to dose-reduction of oxaliplatin or treatment break mostly after about 4 months of therapy.

In contrast, irinotecan containing regimens (FOLFIRI) are more suitable for continuous treatment given their safety profile.

Guidelines recommend continuous treatment of patients with unresectable mCRC until progressive disease (PD), severe toxicity, or the patient’s wish for a treatment break (2,3). In clinical practice, this strategy is frequently followed, but even though progression-free survival (PFS) might reach 12 months in selected patients included in clinical trials, the median duration of therapy rarely reach 9 months due to adverse events and frequent, time-consuming visits to healthcare facilities.

To maintain efficacy while ensuring the best possible QoL for the patients, different strategies regarding the duration and intensity of treatment have been investigated. The following three main strategies are well established:

• Continuous strategy of applying induction treatment until PD with dose reduction if needed;
• Maintenance strategy using induction treatment for a planned period followed by a less intensive regimen until PD;
• Intermittent strategy where treatment is completely stopped after a planned period of induction therapy, patients obtain treatment-free interval (TFI) with re-introduction of the same regimen when progression occurs.

Regarding the maintenance strategy in RAS/BRAF wild-type mCRC, clinical trials have focused on the following approaches: EGFRi monotherapy, 5-FU alone, or the combination of those: EGFRi and 5-FU.

The recently published ERMES trial is the largest randomized trial testing the importance of a maintenance strategy in chemo-naïve patients with RAS/BRAF wild-type mCRC (4). Close to 600 patients started induction therapy with FOLFIRI + cetuximab and patients were randomized upfront to continuous induction therapy (arm A) or maintenance cetuximab after eight cycles of induction regimen (arm B), if no sign of PD. The co-primary endpoints of the ERMES study were non-inferior PFS [hazard ratio (HR): 1.33] in the modified per-protocol (mPP) population (patients receiving more than eight cycles of therapy) and superior safety profile. However, differences in incidence rate of severe adverse events would only have been tested if the null-hypothesis of PFS inferiority was rejected.

A higher than expected number of patients dropped out before starting cycle 9 (at the time of maintenance) and for unknown reason more patients dropped out in arm A 48% vs. 38%. Typically, in randomized trials, 60–70% of patients starting induction therapy continue with therapy beyond 4 months.

In the mPP population, there was a difference in PFS {12.2 (arm A) vs. 10.0 months (arm B); HR: 1.3 [95% confidence interval (CI): 1.03 to 1.64]} but non-inferiority could not be confirmed (the upper limit of 95% CI of HR crossed the non-inferiority boundary of 1.33 with a non-inferiority P value of 0.43). On the contrary, the median OS was numerically but not significantly longer in patients receiving maintenance therapy with cetuximab monotherapy (30.7 vs. 35.7 months, P=0.12). There was no difference in response rates 68% vs. 72% as expected as randomized trials have shown that most and deepest responses occurred within the first 4 months of therapy (5). As projected, patients in arm B had a lower incidence of severe adverse events during maintenance therapy 20% vs. 35%. The authors concluded that the ERMES study did not confirm the non-inferiority of maintenance with cetuximab monotherapy.

Thus, the results of the ERMES study suggest that maintenance strategy should contain a cytotoxic component and this is in line with the current European Society for Medical Oncology (ESMO) guidelines (3). Interestingly, when FOLFIRI is combined with EGFRi in first line, ESMO recommends continuous treatment until PD, given FOLFIRI regimen is not associated with cumulative toxicity.

A number of comparable (Table 1) but also slightly different randomized trials have evaluated different schedules of maintenance therapy with EGFRi.

In six studies (4,6-8,13) patients were randomized before induction therapy, whereas in others (9,10,12), patients without any sign of PD after 12–16 weeks of induction therapy were randomized to EGFRi with or without chemotherapy, or even TFI.

Interpretation of efficacy data from these randomized trials is not straightforward; therefore, it would be obvious but also challenging to perform a systematic review with a meta-analysis to reach a conclusion. Four recent meta-analysis (14-17) included different number of studies, the conclusions were slightly different and none included the ERMES trial. Briefly, Raimondi et al. and Parisi et al. were in favor of the use of 5-FU plus EGFRi (14,15), while Petrelli et al. recommended doublet chemotherapy + EGFRi until PD as the best strategy concerning OS (16). Finally, Mastrantoni et al. concluded that doublet cytotoxic therapy + EGFRi, 5-FU + EGFRi, and EGFRi monotherapy resulted in similar OS (17). However, no study showed a difference in OS.

The development of resistance may be a drawback with continuous exposure to EGFRi therapy (18,19) but this was not supported by two published studies (6,10) which both favored continuous exposure to EGFRi therapy (numerically longer PFS and OS) compared to TFI (after 12 and 16 weeks of induction therapy, respectively). These data are absolutely in contrast to the unpublished data from the IMPROVE study (11). IMPROVE is a small randomized non-comparative phase II study which evaluated induction therapy (FOLFIRI + panitumumab) until PD or an intermittent treatment strategy with eight cycles of induction therapy followed by TFI until PD when another eight cycles of induction regimen was restarted and so on, until PD during therapy. PFS on treatment favored the intermittent arm (11.4 vs. 18.1 months) suggesting that treatment break might be beneficial regarding the tumor biology. Of note, patients receiving intermittent treatment also experienced fewer toxicities. There was no difference in OS (31.0 vs. 32.2 months).

Resistant tumor clones may rapidly grow during EGFRi therapy and decline during EGFRi treatment breaks (20-22). Clinical evidence supports such a strategy in late-line EGFRi rechallenge or re-introduction after prior exposure to EGFRi in first-line therapy and the same biological rationale could be argued for TFI as part of first-line treatment (23). The intermittent strategy of IMPROVE resulted in a remarkable PFS with reduced skin toxicity. A small subgroup was tested with circulating tumor DNA (ctDNA) but only a minor fraction (23%) developed a classic pattern (RAS, PI3K) of resistance. Based on the encouraging results of the IMPROVE study, the authors are planning a confirmatory phase 3 study.

The understanding of resistance mechanisms against anti-EGFR monoclonal antibodies in mCRC is continually evolving. Clinically, anti-EGFR rechallenge, both with and without ctDNA monitoring has been adopted (24). Enhancing patient selection and ctDNA analysis require a thorough understanding of the nature of resistance to anti-EGFR agents considering both the therapy line and the agents anti-EGFR are combined with. The findings are promising but their generalizability is limited due to small sample sizes. To effectively translate these findings into clinical practice, further prospective evidence from large-scale clinical trials is needed to better understand the underlying mechanism and develop strategies to overcome genomic and nongenomic resistance.

In conclusion, several randomized trials and meta-analyses evaluated the effect of maintenance treatment but the optimal strategy still remains unknown. In addition, none of the studies tested or discussed the optimal duration of induction therapy, however, 4 months seems to be a reasonable choice balancing effect and toxicity. Even with the publication of the large ERMES trial, there are still “no size that fits all patients”. Maintenance strategy with 5-FU and EGFRi after 4 months of induction therapy is a safe option, but an intermittent EGFRi-based strategy could be an interesting alternative, especially in patients with left-sided disease. In any case, potential side effects and patient preference should also be an important consideration when deciding whether or not to use maintenance therapy.

There is a need for randomized studies that follow the development of resistance (ctDNA) but until that time, shared decision-making on maintenance treatment must be based on tumor biology, clinical characteristics, and patient preferences.

Acknowledgments

Funding: None.

Footnote

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