In Hong Kong, colorectal cancer (CRC) is the second leading cause of cancer deaths.1 CRC mortality is the highest in patients with metastatic colorectal cancer (mCRC). Nonetheless, recent advancement of endoscopic resection, surgery and systemic chemotherapy have improved the overall survival (OS) rates and surgical outcomes for the patients with resectable mCRC. Despite significant advancement for mCRC treatment, systemic therapy has relatively poor clinical outcomes for a subset of mCRC patients with B-type raf kinase (BRAF) mutation and microsatellite instability-high (MSI-H) phenotype.2,3 Interestingly, immunotherapy is efficacious in patients with MSI-H tumor from the latest findings from the phase 2 CheckMate-142 study.3 The updated results also highlighted the potential role of immune checkpoint inhibitors (ICIs) as first-line defense. Combination therapy of nivolumab and ipilimumab extended the benefits of progression-free survival (PFS) in patients with MSI-H/ deficient mismatch repair (dMMR) tumors.3 Similarly, the BEACON CRC trial further highlighted the benefits of combination targeted therapies for patients with BRAF-mutations.2 At the 2020 Gastrointestinal Cancers Symposium (GICS), experts in the field reviewed the current treatment paradigm of mCRC management particularly for mCRC patients with BRAF mutation and MSI-H.
The current standard of care for the first-line treatment of advanced colorectal cancer
In the past decade, there has been an overall increase in CRC incidence among young adults. Notably, approximately 50% to 60% of patients with CRC have developed mCRC. Critically, the reported median OS for mCRC without treatment is only 6 months.4
Nonetheless, with significant treatment advancement for mCRC consisting of endoscopic resection, surgery and systemic chemotherapy, the OS rates for patients with mCRC have extended from 12 months to an average of 3 years.4 Furthermore, there is an observed increase in the surgical outcomes for patients with resectable metastatic disease. As an example, the majority of mCRC patients who were once not suitable for curative resection may become suitable for surgical resection following the treatment with combination chemotherapy.4
Generally, chemotherapy in mCRC consists of a combination with targeted agents, including fluoropyrimidine (FP) (intravenous 5-fluorouracil (5-FU) or the oral FP capecitabine) in various combinations. Typically, 5-FU is commonly administered with folinic acid (FA) and with either irinotecan or oxaliplatin.5 Comparatively, the combination chemotherapy with 5-FU/LV/oxaliplatin (FOLFOX) is shown to provide a higher response rate, more prolonged progression-free survival (PFS) and better survival rate. 6,7
Although combination chemotherapy remains the preferred option, the evolving availability of novel efficacious cancer drugs, such as ICI, are receiving tractions for mCRC management. Moreover, given the unsatisfactory clinical outcomes for a subset of mCRC patients with mutations following systematic therapy, immunotherapy has gathered significant interest, particularly in the frontline setting. At present, there is a growing body of data demonstrating the successful outcome of using biologics as a second-line defense for treating mCRC. Besides, the Asian EMSO guidelines have updates in using biologics, such as a cytotoxic doublet plus bevacizumab or cytotoxic triplet plus bevacizumab as a first-line treatment for patients with RAS mutant mCRC.8
The initial optimal therapy for mCRC is influenced by an interplay of different aspects, such as the molecular profile of the patient, tumor sidedness and patient factors, such as age, tumor burden, and goal of therapy, performance status, and comorbidities.9 Generally, the evaluation of organ function and concomitant non-malignant diseases determine the therapeutic strategy for patients with mCRC. In fact, other critical elements, such as microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) status and the presence of BRAF mutations would also have an influence on the treatment decisions for patients with mCRC.2,3,9
The BEACON CRC trial demonstrates advances in treating BRAF positive mCRC patients with a doublet/triplet biologic regimen
Increasingly emerging evidence has identified BRAF mutations to be present in 5%-15% of CRC, with a higher mutation rate in right-sided colon cancer. Although BRAF mutations account for only 10%-15% of mCRC, patients with BRAF-V600E mutation demonstrate poor prognosis when treated with the standard treatment, epidermal growth factor receptor (EGFR), for left-sided primary tumors. Primarily, the BRAF gene is present within the MAPK pathway, facilitating the promotion of oncogenic signaling despite the upstream blockade of other molecules, such as anti- EGFR.
Nonetheless, superior efficacy data obtained from the BEACON CRC study illustrated the benefits of using a multitargeted approach, consisting of encorafenib, binimetinib, and cetuximab to treat BRAF V600E–mutated mCRC patients. At the GIS conference, Dr. Scott Kopetz, Professor of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center, presented the updated results from the phase 3 BEACON CRC trial. The main objective of the study was to investigate the efficacy of combined treatment consisting of a BRAF inhibitor, encorafenib, and cetuximab with or without binimetinib, a MEK inhibitor, as a potential treatment for mCRC patients with BRAF-V600E mutation.
In short, the randomized trial consists of 665 patients with BRAF V600E-mutated mCRC, all of whom had disease progression after one or two prior therapies. QOL measures were also incorporated to both the triplet (n=224), doublet (n=220), or control (n=221) studies. Subsequently, analysis of data was compared to the standard of care (SOC) consisting of either irinotecan plus cetuximab or FOLFIRI (leucovorin, calcium folinate, fluorouracil, and irinotecan) with cetuximab.2,10
Dr. Scott Kopetz shared,” We recognize that safety does not always capture the patient experience. That is the rationale for incorporating QOL measures into this study. This is an important component that really helps understand the patient experience and complements the clinical efficacy endpoints.”
Figure 1 shows that the median OS was 9.0 (n=224) and 8.4 (n=220) months with the triplet and doublet targeted treatments, compared to 5.4 months in the control group of patients (n=221). The findings highlighted an overall significantly longer median OS for both the triple (p<0.0001) and double (p=0.0003) targeted therapy. Besides, the objective response rates also reached significantly higher levels with the triplet and doublet than with chemotherapy plus cetuximab (26% and 20% vs. 2%, respectively; p<0.0001 for both experimental arms vs. the control arm). The incidence of grade 3/4 adverse events with the triplet and doublet were comparable to or less than that observed in the control arm (58% and 50% vs. 61%, respectively) despite an approximate 3-fold increase in the median duration of treatment exposure (21 and 19 vs. 7 weeks, respectively).2,10
Secondly, patients on triple regimes showed a similar reduction in the risk of QoL deterioration at 44% (HR=0.56, 95% CI: 0.44-0.71) when compared to the SOC at 45% (HR=0.55, 95% CI: 0.43-0.70) and doublet treatment at 43% (HR=0.57, 95% CI: 0.45-0.72) to 46% (HR=0.54, 95% CI: 0.43-0.69).2,10
Also, the corresponding results were observed in the secondary endpoints, to validate the measurement tools with similar Euro-Quol 5D 5L and patient global impression of change results.2,10
Interestingly, there were no significant differences in QOL between patients in the triplet and doublet groups, but the median time to definitive deterioration was more than twice as long for the triple (4.96 months) and double (4.60 months) regimen as compared to the controls (2.20 months).2,10
Dr. Kopetz. concluded, “In BEACON CRC, triplet and doublet [regimens] demonstrated substantial improvement in patient-reported QOL assessments over the present SOC in patients with BRAF V600E–mutant mCRC whose disease had progressed after one or two prior regimens.”
Dual immunotherapy, nivolumab coupled with low-dose ipilimumab as first-line therapy for MSI-colorectal cancer
Finally, another group of mCRC patients suffering from poor prognosis is MSI-H CRC patients.11 Interestingly, Dr. Heinz-Josef Lenz, MD, of the University of Southern California Norris Comprehensive Cancer Center in Los Angeles, presented an updated safety data from the CheckMate 142 trial, featuring a first-line dual ICI therapy for MSI-H mCRC management.3,11
Initial phase 2 results demonstrated an increase in ORR from 60% to 64%, at a median follow-up of 13.8 months, to a median follow-up of 19.9 months. Interestingly, the updated results of phase 2 CheckMate 142 trial at the median follow-up of 20 months, showed an overall improvement in PFS and OS rates. Mainly, these patients (n=45), did not reach a median PFS or OS, when treated intravenously with nivolumab (3mg/kg every two weeks) and low dose ipilimumab (1mg/kg every six weeks).3
Furthermore, at 15 months, the PFS and OS rates were 75% and 84%, respectively. Besides, the disease control rate was at 78%, with 84% of patients experiencing tumor shrinkage at the target lesion.3,11
Dr. Lenz commented, “Nivolumab and low-dose ipilimumab demonstrate clinically meaningful and durable benefits and may present an option for first-line treatment for MSI CRC.”
Additionally, Dr. Lenz shared his preference for the targeted therapy by stating, “The incredible complete RR and ORR seen are never seen with chemotherapy, and it is very well tolerated, so if I have a choice, I would start with nivolumab-ipilimumab in first-line MSI-H.”
Moving towards immunotherapy as an initial regimen for addressing poor mCRC prognosis
Recently, a shift in the treatment paradigm towards the use of personalized therapy, particularly in treating patients with BRAF mutation status and MSI status, is fast gaining attention. As seen from the EMSO Asia updated guidelines and the FDA approval of pembrolizumab and nivolumab ± ipilimumab for the treatment of subset patients with mCRC, the combination immunotherapy serves as an additional option for them.
In conclusion, immunotherapy, specifically ICI, may potentially serve as an alternative resource for improving the treatment outcomes for all patients with mCRC.12