A Brief History of Metastatic Colon Cancer

The treatment of metastatic colorectal cancer has evolved in the last several decades with the advent of new systemic therapies. This has led to improved patient outcomes and survival. While in many cases, metastatic colorectal cancer remains an incurable disease, further research and understanding of the molecular drivers of colorectal cancer will continue to advance the care of our patients.

Shikha Jain, Associate Professor, Director of Communication Strategies, University of Illinois Chicago Lucia D, Notardonato, Hematology/Oncology Fellow, University of Illinois

Colorectal cancer (CRC) continues to be a significant global public health challenge. In 2020, it was estimated that there were 1.9 million new CRC cases and 0.94 million CRC related deaths worldwide. With a global incidence of 10 per cent, it is the third most common cancer, and the second most common cause of global cancer-related deaths. It has been projected that the global incidence rate will continue to rise to

3.2 million by 2040. Fortunately, there have been significant advancements in the treatment of CRC in the last several decades such as improved surgical techniques, new therapeutics, a better understanding of precision oncology and next generation sequencing, and the adoption of metastatectomy and even liver transplant in certain patient populations with oligometastatic disease. When CRC is diagnosed in early stages, it is highly treatable and often curable. In the United States, the 5-year survival rate for localised and regional CRC is 92 per cent and 72 per cent, respectively. However, approximately 20 per cent of CRC presents as metastatic at time of diagnosis, which portends a poor prognosis with a 5-year survival rate of 14 per cent. While chemotherapy and surgical resection have shown to prolong survival in oligometastatic disease confined to a single organ, unresectable metastatic CRC poses a significant challenge for significant improvements in advances in overall survival benefits. The mainstay of treatment for unresectable metastatic CRC is systemic therapy. Here we will review current systemic treatment options for unresectable metastatic CRC.

Chemotherapy

The most used class of first-line treatment for unresectable metastatic CRC is chemotherapy. Intravenous fluorouracil, a fluoropyrimidine antimetabolite, was the first chemotherapy to be used for CRC starting in the late 1950s. It took an additional forty years before an oral prodrug of fluorouracil, capecitabine, was to be introduced to the chemotherapy arsenal. Around the same time in the early 2000s, two additional chemotherapy agents, oxaliplatin and irinotecan, were being evaluated in combination with fluorouracil for first-line treatment of metastatic CRC. Several randomised controlled trials demonstrated that FOLFOX (fluorouracil + leucovorin + oxaliplatin) and FOLFIRI (fluorouracil + leucovorin

+ irinotecan) had higher response rates and improved progression-free survival compared to fluorouracil monotherapy Overall survival was not shown to be improved compared to fluorouracil monotherapy in all studies, but this was attributed to significant cross-over between the groups. Several studies have demonstrated that FOLFOX and FOLFIRI are similarly effective as first-line treatment of metastatic CRC when compared head-to-head. This has established two lines of chemotherapy regimens that can be sequentially given after progression occurs. Lastly, capecitabine has been shown to be interchangeable with fluorouracil in either chemotherapy combination regimens. Two meta-analyses have demonstrated that there are no differences in overall survival between CAPOX (capecitabine + oxaliplatin) vs FOLFOX or CAPIRI (capecitabine + irinotecan) vs FOLFIRI.

Biologics

In addition to chemotherapy, biologic agents play an integral role in treatment for metastatic CRC. Vascular endothelial growth factor (VEGF) has been shown to be a key mediator in tumour-induced angiogenesis in CRC. Bevacizumab is a humanised anti-VEGF monoclonal antibody that was first approved for metastatic CRC in combination with fluorouracil-based chemotherapy in 2004. Several studies have demonstrated improved progression-free survival with adding bevacizumab to fluorouracilbased chemotherapy. Bevacizumab has been approved for the first-line setting, the second-line setting, or to be continued into the second-line setting if the chemotherapy backbone has been changed. Other VEGF inhibitors include ramucirumab, a humanised anti-VEGF-R2 monoclonal antibody, and ziv-aflibercept, a recombinant fusion protein that acts as a VEGF inhibitor. Both ramucirumab and ziv-aflibercept have been approved in the second-line setting in combination with FOLFIRI after first-line FOLFOX based on research that demonstrated improved progression-free survival and overall survival compared to FOLFIRI + placebo. It is important to note that VEGF inhibitors need to be held before and after surgery for at least 4 weeks as they can lead to delayed wound healing.

EGFR inhibitors also have a role in treatment in certain patients with metastatic CRC. Cetuximab and panitumumab are EGFR inhibitors that have been approved for RAS/ BRAF wild-type (WT) metastatic CRC in combination with chemotherapy. In a randomised controlled trial, there was no significant difference in progressionfree survival or overall survival in patients with KRAS WT metastatic CRC with first-line EGFR inhibitor (cetuximab) with chemotherapy compared to first-line VEGF inhibitor (bevacizumab) with chemotherapy. Additionally, EGFR inhibitors combined with chemotherapy are recommended in the first-line for left-sided, RAS/BRAF WT CRC. This has been postulated to be due to different embryologic origins, vascular supply, and microenvironments that lead to different gene alterations seen between right- and left-sided CRC. A known mechanism of resistance that occurs with patients treated with chemotherapy and an EGFR inhibitor is acquisition of a RAS-mutant clone. It has been hypothesised that when next line treatment is used without an EGFR inhibitor, the acquiredRAS mutant clone cells will decay while the original RAS WT clones may proliferate. Thus, leading to the possibility of “re-challenging” the cancer by re-introducing an EGFR inhibitor when the RAS-mutant clone is no longer present as assessed by liquid biopsies (i.e. KRAS/BRAF WT metastatic CRC on liquid biopsy).

With a global incidence of 10 per cent, CRC is the third most common cancer, and the second most common cause of global cancer-related death. It has been projected that the global incidence rate will continue to rise to 3.2 million by 2040.

Immunotherapies

Immunotherapy has not been as successful in metastatic CRC compared to other solid tumour malignancies. However, immunotherapies are beneficial in the 5 per cent of metastatic CRC that are MSI-H/ MMR deficient. Three immunotherapy regimens have been approved in the first-line setting of MSI-H/MMR deficient metastatic CRC : (1) pembrolizumab, (2) nivolumab, and (3) nivolumab + ipilimumab. Both pembrolizumab and nivolumab are antiPDL1 monoclonal antibodies while ipilimumab is an anti-CTLA-4 monoclonal antibody. In a randomised controlled trial comparing pembrolizumab vs standard chemotherapy in the first-line setting of MSI-H/MMR deficient metastatic CRC, pembrolizumab demonstrated significantly improved progression free survival with a durable response. A single arm phase II trial demonstrated durable clinical benefit in patients treated with combination nivolumab + ipilimumab in the firstline setting. There has been no head-tohead comparison assessing nivolumab monotherapy vs nivolumab + ipilimumab in the first line setting in this patient population. However, one study did demonstrate improved clinical benefit with combination nivolumab + ipilimumab vs nivolumab monotherapy in the chemotherapy-refractory setting.

Targeted therapies

While BRAF V600E variant CRC only comprises 5-10 per cent of metastatic CRCs, this particular subtype confers a poor prognosis with less benefit from standard chemotherapy regimens. An important mechanistic discovery was recently made that demonstrated that BRAF inhibition leads to upregulation of EGFR signaling in the BRAF mutant clones. This led to a phase III trial examining patients with BRAF V600E metastatic CRC who had progressed on at least one prior line of treatment that demonstrated improved overall survival with the combination of encorafenib (BRAF inhibitor) + cetuximab. Current trials are investigating the efficacy of encorafenib + cetuximab in the first-line setting with and without chemotherapy.

Other approved lines

In the third- and fourth-line settings, oral regorafenib, a multi-kinase inhibitor, and oral trifluridine-tipiracil, a fluropyrimidine derivative, have both been approved for metastatic CRC. Unfortunately, both have demonstrated a modest clinical benefit of less than two months in overall survival compared to supportive care.

Upcoming treatments

In the coming years, there will likely be more targeted therapy regimens available for metastatic CRC. Here, we will briefly highlight some of this promising research. In the last year, sotorasib and adagrasib were recently approved for the use of KRAS G12C mutated advanced lung cancer. KRAS G12C mutations are seen in about 3-4 per cent of metastatic CRC. There are two ongoing randomised phase III trials investigating the role of these agents in combination with EGFR inhibitors in non-first line settings compared to standard of care regimens in KRAS G12C metastatic CRC. Additionally, HER2 gene amplification is also seen in 2-3 per cent of CRC. There have been several small studies demonstrating clinical benefit with HER2 inhibition in the chemorefractory setting for CRC. Most of these studies utilised a dual HER2 blockade, such as trastuzumab, an anti-HER2 monoclonal antibody, in combination with lapatinib, a tyrosine kinase inhibitor of HER2 and EGFR1, or trastuzumab with pertuzumab, another HER2 monoclonal antibody. Most recently, trastuzumab-deruxtecan, an antibody-drug conjugate of a HER2 monoclonal antibody with a topoisomerase I inhibitor, was shown in a single arm, phase II study to have clinical benefit in the chemo-refractory setting of HER2 amplified metastatic CRC. Future randomised clinical trials will be needed to determine the efficacy of anti-HER2 treatment in the first-line setting.

Conclusion

While there have been significant advancements in treatment options for metastatic CRC in the last few decades, further research is imperative to continue to improve patient outcomes. Molecular profiling will continue to play an integral role in developing new treatment strategies and selecting the optimal treatment for a patient on a personalised level.

References are available at www.asianhhm.com

Dr. Shikha Jain is a board-certified hematology and oncology physician. She is a tenured associate professor of medicine in the Division of Hematology and Oncology at the University of Illinois in Chicago. She is the Director of Communications Strategies in Medicine and the Associate Director of Oncology Communication and Digital Innovation for the University of Illinois Cancer Center. Dr. Jain is the founder and President of the 501(c)(3) nonprofit Women in Medicine® and founder and chair of the Women in Medicine Summit. She is the CEO and Co-Founder of the action, advocacy and amplification organization IMPACT. Dr. Jain was named one of Medscapes 25 Rising Stars in Medicine in 2020, one of Modern Healthcare's Top 25 Emerging Leaders in 2019, and was also awarded the Rising Star award by the LEAD Oncology Conference in 2019.

She is a nationally renowned keynote speaker and has written for several national publications including USA Today, CNN, Good Morning America, Scientific American, The Hill, US News, Newsweek and has been interviewed in the New York Times and Washington Post. She is a regular tv contributor to FOX 32 and has also been a guest on ABC7, CBS, WGN and other national media outlets.