Continued Development of Targeted Therapies Aims to Address Unmet Needs in CRC


John L. Marshall, MD, discusses the identification of targetable subsets of patients with advanced CRC, unmet needs that remain to be addressed for patients with advanced CRC, and the continued need for a multidisciplinary approach in treating patients across the gastrointestinal cancer spectrum.

John L. Marshall, MD

John L. Marshall, MD

The continued development of treatments for patients with HER2-positive metastatic colorectal cancer (CRC) served as another milestone in the effort to create more personalized approaches for different subsets of patients, according to John L. Marshall, MD.

In January 2023, the FDA granted accelerated approval to tucatinib (Tukysa) in combination with trastuzumab (Herceptin) for adult patients with RAS wild-type, HER2-positive unresectable or metastatic CRC that has progressed after treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. The approval was supported by data from the phase 2 MOUNTAINEER trial (NCT03043313), which showed that patients treated with the doublet achieved an overall response rate of 38% (95% CI, 28%-49%).

Outside of patients with HER2-positive CRC, Marshall pointed to RAS mutations as another actionable target. Although KRAS G12C inhibitors could affect the CRC treatment paradigm, he said KRAS G12C–mutated CRC makes up only a small proportion of patients, and targeted therapies for other RAS mutations are under investigation.

“What we are excited to see is this wave of new therapies targeting RAS [mutations]. There are a lot of clinical trials and new approaches for [targeting] RAS. The biggest unmet need [in CRC] is how to treat [patients who] have RAS mutations. [With ongoing research], we may be on to something,” Marshall said.

In an interview with OncLive®, Marshall, chief of Hematology and Oncology, professor of medicine and oncology, and director of the Otto J. Ruesch Center for the Cure of Gastrointestinal Cancers at the Lombardi Comprehensive Cancer Center of Georgetown University in Washington, D.C., discussed his presentation from the 8th Annual School of Gastrointestinal Oncology (SOGO) on identifying targetable subsets of patients with advanced CRC, the unmet needs that remain to be addressed for patients with advanced CRC, and the continued need for a multidisciplinary approach in treating patients across the gastrointestinal (GI) cancer spectrum.

OncLive: What points did you hope to convey in your presentation on targetable subsets in advanced CRC at SOGO?

Marshall: One of the good things about being the head of a meeting is you get to pick your favorite topics to review. Therefore, I reviewed the new targetable lesions that are being seen in patients with metastatic CRC. Those genetic lesions are, as we know, microsatellite instability [MSI], RAS [mutations], and BRAF [mutations]. However, the newest member [of targetable lesions] is HER2. [We have generated] exciting clinical data targeting [HER2] in those 3% to 5% of patients [with CRC] who are HER2 positive.

What unmet needs remain regarding targeted therapies for patients with CRC? How could these unmet needs be addressed?

CRC has a very common mutation in RAS. There are [many] different RAS mutations, and there is a lot of excitement surrounding KRAS G12C, which is a mutation where we have new [targeted] therapies, but the [KRAS G12C mutations] are not that common in CRC. We have many other RAS mutations that are more common.

What other presentations from the SOGO were intriguing to you?

On our list for new, exciting things that are on the horizon for GI cancer, [perhaps] the most important [topic] is how to extend immune therapy approaches to more patients. We know about MSI and [its] impact on immune therapy. We know that tumor mutational burden might help; we know PD-L1 [expression] does not help very much. So how do we get more [immune therapy] out there?

One of the leading therapeutic angles is CAR T-cell therapy or other bispecific monoclonal antibodies. How do we tailor the immune system to go fight a cancer? What we heard at SOGO [was updates] on where we are in that space in GI cancers.

How did the agenda for the SOGO reinforce the idea of collaborating across disciplines to provide comprehensive care for patients with GI cancer?

We have spent so much of our last 3 years [communicating virtually on computers]. SOGO is all about getting together and collaborating [in person]. We know that [treating patients with] GI cancer is a team sport. You need surgeons, interventional radiologists, radiation oncologists, nurses, social workers, [and] nutritionists, along with medical oncologists. Getting together is so important to read the room and read each other's feelings about [the treatment of these patients].

Through our tumor board and our challenging case-based presentations, we hoped that people would regain that feeling of community and working together to learn from one another about the small subtleties that will make us all better doctors.

Looking back to the 2023 Gastrointestinal Cancers Symposium, what were some of the most important data presented at that meeting?

We had a lot [of new information] come out of the 2023 Gastrointestinal Cancers Symposium. We learned that when you combine trifluridine/tipiracil [TAS-102; Lonsurf] and bevacizumab [Avastin], there were improved outcomes [for patients with refractory metastatic CRC in the phase 3 SUNLIGHT trial (NCT04737187)].

We found a new marker for gastric cancer: Claudin 18.2 (CLDN18.2). There were other data around pancreas cancer and gastric cancer that were important and practice-changing. The 2023 Gastrointestinal Cancers Symposium had more data in it than the previous 3 [meetings] combined. It was a very rich meeting for new data presented this year.

Are there any data you are most looking forward to seeing at the 2023 ASCO Annual Meeting?

The [phase 2/3] PROSPECT trial [NCT01515787] is a clinical trial [in patients with locally advanced] rectal cancer. We have been participating in it for years now, and we are expecting it to be presented at the 2023 ASCO Annual Meeting. This study, if positive, would create a new pathway where patients no longer need to receive radiation for rectal cancer. [We are hoping] that this study is positive, and I cannot wait to see [the data].


FDA grants accelerated approval to tucatinib with trastuzumab for colorectal cancer. News release. FDA. January 19, 2023. Accessed May 9, 2023.

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