Optimizing the bevacizumab and anti-EGFR sequence in RAS wildtype metastatic colorectal cancer: The switch maintenance concept

With the increasing number of therapeutic options for patients with metastatic colorectal cancer (mCRC), questions arise on the optimal treatment sequence. The FIRE-4 study assessed the efficacy of an early switch to maintenance (5-FU/FA plus bevacizumab) during 1st-line therapy (FOLFIRI plus cetuximab) and re-challenge with cetuximab (part 2) in a later treatment line. The first randomisation of this study evaluates whether an early switch from cetuximab to bevacizumab during maintenance therapy could delay the disease progression. Unfortunately, however, no benefit in either PFS, OS or overall response rates (ORR) was observed with this strategy.

Palliative chemotherapy for metastatic colorectal cancer (mCRC) has undergone substantial changes in recent years. Based on the results of the PARADIGM study, the anti-EGFR agent panitumumab rather than bevacizumab seems to be the preferred targeted therapy to use upfront, in combination with FOLFOX, in patients with left-sided RAS wild-type mCRC. The results of this trial are consistent with previous findings from PEAK, FIRE-3 and C80405. Results of the PANAMA trial indicated a continuation of anti-EGFR with maintenance 5FU is better than 5FU alone in patients with RAS wild-type mCRC treated with induction chemotherapy + anti-EGFR. With the increasing number of therapeutic options, the question of optimal treatment sequence arises, and this issue is being addressed by a number of studies, including FIRE-4. The FIRE-4 study tested the efficacy of an early switch to maintenance (5-FU/FA plus bevacizumab) during 1st-line therapy (FOLFIRI plus cetuximab) and re-challenge with cetuximab (part 2) in later-line treatment. The first randomisation evaluates if an early switch from cetuximab to bevacizumab during maintenance therapy may prolong PFS in RAS-wild-type mCRC patients.

Methods

This randomised controlled, open-label phase-III study enrolled mCRC RAS wild-type patients untreated  for metastatic disease. In total, 84% of the enrolled patients were left-sided. These patients received FOLFIRI (Irinotecan 180 mg/m², folinic acid 400 mg/m², 5 5-FU 3mg/m² within 48hrs) + cetuximab (cetuximab 400mg/m² loading dose followed by 250mg/m² weekly) every two weeks at the standard dosing schedule (induction). In arm A, FOLFIRI plus cetuximab was continued every two weeks until progression or intolerable toxicity. In arm B, however, patients received eight cycles of FOLFIRI plus cetuximab (in case of tumour response) or twelve cycles (in case of stable disease) followed by maintenance with 5-FU/FA plus bevacizumab (5mg/kg) every two weeks until disease progression or intolerable toxicity. Both groups received a second line of anti-EGFR-free therapy. Later, patients were again randomised to FOLFIRI + cetuximab or physician’s choice (re-induction). OS after the second randomisation (part 2) was evaluated as a primary endpoint. During the 2022 world congress on gastrointestinal cancer, PFS data in first-line (part 1), a secondary study endpoint of the study, were reported. Other secondary endpoints included overall response rate (ORR) and overall survival  (OS).

Results

From August 2015 to January 2021, 672 patients were randomised of whom 656 were assigned to treatment (327 arm A and 329 in arm B). The primary analysis of the overall study population demonstrated a comparable outcome data in both treatment arms. As such, there was no difference in efficacy after the first randomisation. The median PFS was reported at 10.7 months in arm A (FOLFIRI plus cetuximab continuation) and at 11.3 months in arm B (FOLFIRI plus cetuximab + maintenance with 5-FU/FA plus bevacizumab) (HR:0.92; p=0.36). There was also no difference in OS between the two arms  with a hazard ratio (HR) of 1.03 (p=0.81). In the treated population (n=656), ORR was 59.9 vs. 58.7% in arms A vs. B (OR: 1.05[0.77-1.44]; p=0.75). The disease control rate was 74.9 vs. 75.1% in arms A vs. B (OR:0.99[0.70-1.41; p>0.99). Among evaluable patients (n= 526), the ORR was 75.7 vs. 72.3% in arms A vs. B, with corresponding disease control rates of 94.6 and 92.5% (OR:1.41[0.70-2.87]; p=0.38). Among the 643 patients who were evaluable for sidedness, 84% (n=539) proved to have a left-sided tumour and 16% (n=104) with right-sided tumours. In left sided tumours, comparable results were obtained in both treatment arms (A vs. B) with regard to ORR (78.8% vs. 78.0%), PFS (11.5 months vs. 11.6 months), and OS (33.2 months vs. 35.6 months). In right-sided tumours, efficacy data (arms A vs. B) were generally less favourable. ORR was numerically superior with continued application of cetuximab in arm A (56.8% vs. 42.2%, p=0.27). However, survival data appeared to be more favourable in the switch maintenance arm (B) with regard to PFS (5.5 months vs. 7.4 months, P=0.38) and OS (12.5 months vs. 21.2 months, p=0.27).

Conclusion

FIRE-4 confirms the efficacy of FOLFIRI plus cetuximab as first-line treatment of patients with RAS wild-type mCRC. High response rates, of up to 75% were observed with doublet plus anti-EGFR in evaluable populations. There was no benefit  in ORR, PFS or OS when opting for an early biological switch strategy (arm B). In patients with left-sided tumours, continued application of cetuximab induced comparable efficacy as an early switch from FOLFIRI cetuximab to maintenance therapy with 5-FU plus bevacizumab. In right-sided tumours, some differences were seen, but this did not reach the level of statistical significance (survival data numerically in favour of the bevacizumab switch-maintenance arm).

Reference

Heinemann V, von Weikersthal LF, Fuchs M, et al. FIRE-4 (AIO-KRK-0114): Randomized study for a switch maintenance concept with 5-FU plus bevacizumab after induction treatment with FOLFIRI plus cetuximab versus continued treatment with FOLFIRI plus cetuximab – secondary endpoint. Presented at ESMO WGCI 2022; Abstract SO-16.