Targeted Therapy, Vaccines, and Second-Generation Checkpoint Inhibitors Seek to Redefine mCRC Treatment

Therapies such as trifluridine/tipiracil (TAS-102; Lonsurf) plus bevacizumab (Avastin) and fruquintinib (Fruzaqla) have expanded the therapeutic options available to patients with refractory metastatic colorectal cancer (mCRC), according to Arvind Dasari, MD, MS, who added that continued clinical trial participation is needed to further propel the development of novel therapies.

“A lot of exciting work is being done and we are eagerly looking forward to seeing the results [of these ongoing trials] in the near future,” Dasari said.

In an interview with OncLive®, Dasari discussed some of the exciting areas of drug development in mCRC and highlighted the potential movement of targeted therapies into earlier lines of treatment. Dasari is an associate professor in the Department of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston.

OncLive: What are some trends you’re seeing in novel drug development in refractory mCRC?

Dasari: It’s important to remember that most novel drug development initially occurs in the refractory setting or later lines of therapy. Based on efficacy, these therapies are then often moved to earlier lines of treatment, which is a pattern we’ve seen repeatedly. Currently, efforts are focused on shifting some therapies, initially developed in the refractory setting, to earlier lines of treatment. This includes anti-BRAF and anti-HER2 therapies.

Another significant focus is on developing truly novel therapies, especially those targeting mutations that were previously considered [undruggable] such as KRAS and RAS mutations. Significant progress has been made with KRAS G12C mutations, and these initial breakthroughs are now expanding to other specific KRAS mutations, like KRAS G12D. We are also seeing the development of more comprehensive pan-KRAS and pan-RAS inhibitors, which are currently in early development stages and hold much promise.

What will be important to keep in mind as more clinical trials become available for patients with refractory mCRC?

One of the key takeaways from both the phase 3 SUNLIGHT (NCT04737187) and FRESCO-2 (NCT04322539) trials is how quickly they enrolled, [highlighting the ongoing need for more treatment options in patients with refractory colorectal cancer]. By far the biggest unmet need is the fact that we are not achieving durable responses or stability of cancer in this setting.

It’s encouraging to see efforts being made to address this limitation, but it’s crucial to remember that these patients often have extensive metastatic disease and have undergone multiple lines of therapy. [Therefore, quality of life remains a top priority. While developing new therapies it’s essential to focus on efficacy while ensuring that these treatments are well tolerated and do not negatively affect quality of life].

What role does immunotherapy play in mCRC?

No discussion around drug development can happen these days without mentioning immunotherapy. However, in mCRC progress is somewhat behind other cancers, such as melanoma or kidney cancer, where immune checkpoint inhibitors are used broadly. Currently, checkpoint inhibitor use in mCRC is largely limited to microsatellite instability–high patients.

[Emerging data suggest potential benefits when combining checkpoint inhibitors with VEGF TKIs, particularly in specific subsets, such as patients without liver metastases. This area needs further exploration. Additionally, second-generation checkpoint inhibitors, like the botensilimab/balstilimab combination agents, are showing some promising activity and warrant further investigation.

There are also early-stage efforts investigating vaccine-based and cellular therapy approaches, which, if successful, could be game changers. These are some of the key areas where exciting research is ongoing, and we eagerly anticipate the results soon.

What is your take-home message regarding the current state of later-line mCRC treatment?

The armamentarium is expanding, which is exciting. [In just the past few years we’ve added therapies like trifluridine/tipiracil plus bevacizumab and fruquintinib to the salvage setting. The sequencing of these treatments depends on various factors, including patient characteristics, clinical context, and patient preferences]. As we continue to develop novel therapies it’s important to consider enrolling eligible patients into clinical trials to build on these successes. We’re also looking to develop novel therapies, so please consider enrolling patients onto clinical trials, so that we could further expand on these successes.