European society for medical oncology (ESMO) annual meeting 2024: key developments in the treatment paradigm for metastatic colorectal cancer

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ONCOLOGY

Medical writer: Adiya Ualiyeva | Last updated: 17 December 2024 | In: Oncology

Article Keywords

metastatic colorectal cancer, novel treatments, RAMTAS/IKF643 trial, OrigAMI-1 trial, BREAKWATER trial

Colorectal cancer (CRC) is a substantial healthcare burden globally, with over 1.9 million new cases and over 930,000 deaths in 2020.¹ Metastatic CRC (mCRC) has a particularly poor prognosis, with a 5-year survival rate of only 14%.² Here, we report key findings of three abstracts investigating novel treatment strategies for mCRC, from the European Society for Medical Oncology (ESMO) Annual Meeting 2024.

Randomised phase III trial of ramucirumab in combination with TAS102 (trifluridin/tipiracil) vs TAS102 monotherapy in heavily pretreated metastatic colorectal cancer: The RAMTAS/IKF643 trial of the German AIO (AIO-KRK-0316)

Limited therapeutic options are available for patients with chemotherapy (CTx)-refractory mCRC. This randomised phase III trial examined the efficacy and safety of adding the anti-angiogenic agent ramucirumab (RAM) to trifluridin/tipiracil (FTD/TPI), the current standard of care (SOC) in patients progressing after two lines of combination therapies.³ A total of 428 previously treated mCRC patients were randomised (1:1) to receive FTD/TPI with RAM (Arm A; n=213) or without RAM (Arm B; n=215).³ Previous treatments included oxaliplatin, irinotecan, fluoropyrimidin, anti-epidermal growth factor receptor (EGFR) antibodies (Abs) and anti-angiogenics.³ The median age was 62 years (range 25–90); with 45.1% females, 61.7% with RAS mutations and 67.1% with left-sided tumours.³ Overall, 62.6% of patients had received >2 prior lines of treatment.³

The primary endpoint was overall survival (OS), and secondary endpoints included disease control rate (DCR), progression–free survival (PFS) and safety.³ The median OS was similar between the two arms, measuring 7.46 months in Arm A vs 7.06 months in Arm B (HR=0.871, p=0.1941), with OS improvements observed in female patients (HR=0.712; p=0.0371) and those with left-sided tumours (HR=0.770; p=0.0469). The median PFS improved, 2.37 months in Arm A vs 2.07 months in Arm B (HR=0.774; p=0.011).³ Likewise, the DCR in Arm A was higher when compared to Arm B, 39.4% vs 31.6%, respectively(p=0.0336).³ No new safety signals emerged.³

Although the trial did not meet its primary endpoint of improved OS in the overall population, adding RAM to FTD/TPI improved OS in certain subsets including female patients and patients with left-sided tumours. These findings support personalisation of treatment decisions in mCRC patients who have failed multiple lines of standard therapy.

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Amivantamab plus FOLFOX or FOLFIRI in metastatic colorectal cancer: Results from OrigAMI-1, an open-label, phase Ib/II study

Amivantamab (AMI) is a bispecific antibody detected at the EGFR and mesenchymal-epithelial transition (MET) receptor-directed bispecific antibody with immune cell-directing activity.⁴ Due to its unique mechanism of action, AMI is thought to improve efficacy and safety when combined with SOC FOLFOX* or FOLFIRI^† CTx for RAS/RAF wild-type (WT) mCRC.⁴

The phase Ib/II open-label study OrigAMI-1 (NCT05379595) assessed the efficacy and safety of AMI combined with FOLFOX (modified FOLFOX6) or FOLFIRI.⁴ As of April 8 2024, a total of 44 RAS/RAF WT mCRC patients who had received ≤1 prior lines in the metastatic setting and who were naïve for EGFR-Abs, oxaliplatin, and irinotecan, received either AMI + FOLFOX (n=21) or AMI + FOLFIRI (n=23). The median follow-up was 3.9 months and 4.4 months, respectively.⁴ The median age was 62 years; and most patients had left-sided tumours (n=13 patients receiving AMI + FOLFOX and n=20 patients receiving AMI + FOLFIRI).⁴ Responses were assessed per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1.⁴ The best timepoint response rate was 63% (10/16) for AMI + FOLFOX-treated patients and 48% (11/23) for AMI + FOLFIRI-treated patients.⁴ Among responders, the median duration of response was not estimable (NE) in the AMI + FOLFOX arm, and measured 6.5 months in the AMI + FOLFIRI arm.⁴ A DCR of 88% and 87% was achieved with AMI + FOLFOX and AMI + FOLFIRI, respectively.⁴ The median PFS among AMI + FOLFOX-treated patients was NE and 7.4 months in AMI + FOLFIRI-treated patients.⁴ The most frequent adverse events were rash and neutropenia, with no new safety signals reported.⁴

This study demonstrated encouraging, and durable anti-tumour activity of AMI in combination with FOLFOX or FOLFIRI, with a manageable safety profile among EGFR-Abs naïve, RAS/RAF WT mCRC patients.⁴

Encorafenib + cetuximab + FOLFIRI for BRAF^V600E-mutant mCRC: Updated results from the BREAKWATER safety lead-in

The BREAKWATER trial (NCT04607421) is an ongoing trial evaluating encorafenib + cetuximab (EC) ± CTx (FOLFIRI*/modified FOLFOX6^†) vs SOC CTx among treatment-naïve patients with BRAF^V600E-mutant mCRC.⁵ This study reported the safety lead-in (SLI) results of the BREAKWATER trial.⁵ As of 22 December 2023, 30 patients (n=12 in 1L and n=18 in the 2L) were enrolled in the EC + FOLFIRI cohort of the SLI. Eligible patients had BRAF^V600E -mutant mCRC (blood or tumour tissue), ≤1 prior systemic treatment for mCRC and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.⁵ Patients enrolled were naïve for prior BRAF- & EGFR-inhibitors as well as oxaliplatin and irinotecan.⁵

The primary endpoint was the incidence of dose-limiting toxicities (DLTs). Safety and anti-tumour activity were among the secondary endpoints.⁵ One patient had a DLT of grade 4 neutropenia lasting for >7 days.⁵ All-causality serious adverse events occurred in 46.7% of patients.⁵ The confirmed objective response rate by blinded independent central review (BICR) was 83.3% in the 1L and 44.4% in the 2L.⁵ Median PFS by BICR was NE in the 1L and 12.6 months in the 2L.⁵ Median OS was NE in the 1L and 19.7 months in the 2L, respectively. No new safety signals were identified.⁵

EC + FOLFIRI was generally tolerable with promising anti-tumour activity in the BREAKWATER SLI.⁵

^*FOLFIRI, leucovorin calcium, fluorouracil, and irinotecan hydrochloride.
^†FOLFOX, leucovorin calcium, fluorouracil, and oxaliplatin.

References

World Health Organization. Available online: https://www.who.int/news-room/fact-sheets/detail/colorectal-cancer. Last accessed: 8 October 2024.

Leowattana W, et al. World J Gastroenterol. 2023;29(10):1569–88.

Kasper-Virchow S, et al. Ann Oncol. 2024;35(S2):S1218.

Pietrantonio F, et al. Ann Oncol. 2024;35(S2):S434.

Tabernero, J. et al. Ann Oncol. 2024;35(S2):S435–6.

Disclaimer

This article is not medical advice. Patients should seek personal assessment by a licenced specialist. Physicians are recommended to read the full publication(s) as cited in the article before making medical decisions. This article does not supersede nor replace the published article(s).