Overview

In this blog, we feature five actively recruiting clinical trials for colorectal cancer patients with minimal residual disease (MRD) after curative-intent treatment. MRD refers to a very small number of cancer cells that remain in the body during or after treatment that cannot be detected using traditional scans or imaging.

Highlights

• This blog features five actively recruiting clinical trials for colorectal cancer patients with minimal residual disease (MRD) and tips from patient advocates for people looking for MRD clinical trials.
• We highlight the eligibility criteria, goals, study design, and primary endpoints for each trial.
• MRD refers to a very small number of cancer cells that remain in the body during or after treatment that cannot be detected using traditional scans or imaging.

Resources

Clinical trials are critical to finding a cure for colorectal cancer. As an advocacy organization dedicated to supporting and empowering a community of patients, caregivers and families, Fight CRC has partnered with COLONTOWN to deliver a monthly blog series highlighting everything patients need to know about clinical trials and the best treatment options available.

More Fight CRC Resources:

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Introduction

This month we feature clinical trials for colorectal cancer patients with minimal residual disease (MRD) after curative-intent treatment. MRD describes microscopic residual disease, where a very small number of cancer cells may remain in the body during or after treatment. MRD cannot be seen using traditional scans and imaging (such as a CT scan, PET scan, or MRI). Instead, detecting MRD requires highly sensitive laboratory methods. The presence of circulating tumor DNA (ctDNA), or small pieces of DNA released by tumor cells into the bloodstream, in a blood sample can be used to identify MRD.

Colon Adjuvant Chemotherapy Based on Evaluation of Residual Disease (CIRCULATE-North America)

NCT05174169

CIRCULATE-North America (open in the United States and Canada) is an actively enrolling (714/1912 slots filled), multi-center phase II/III trial for non-metastatic colon cancer patients.

Who is eligible? Patients must have stage IIB/C or stage III microsatellite stable (MSS) colon cancer with successful surgical removal of the primary tumor with clear margins.

What is the goal of this study? This trial aims to determine whether ctDNA status after surgery can be used to make decisions about adjuvant chemotherapy in stage II/III colon cancer patients.

For example, non-metastatic colon cancer patients with no detectable ctDNA (ctDNA negative) after curative-intent surgery are at a lower risk for recurrence and may not need adjuvant chemotherapy, while patients with detectable ctDNA (ctDNA positive) are at a higher risk for recurrence and may need more aggressive adjuvant therapy. This trial tests these ideas and will compare outcomes between different arms in the trial.

What can patients expect? Patients are given a Signatera™ test, a tumor-informed (personalized) blood test, to determine their ctDNA status (positive or negative) after surgery.

Patients who are ctDNA negative (cohort A) are randomized to one of the following arms:

• Six to twelve cycles of FOLFOX or four cycles of CAPOX (standard of care)
• Serial ctDNA monitoring without adjuvant chemotherapy (experimental)

Patients who are in cohort A (ctDNA negative) that have a positive ctDNA test at any point are allowed to cross over to cohort B (ctDNA positive).

Patients who are ctDNA positive (cohort B) are randomized to one of the following arms:

• Twelve cycles of FOLFOX or eight cycles of CAPOX (standard of care)
• Twelve cycles of FOLFIRINOX (experimental)

What is being measured? The primary endpoints are time to positive ctDNA test (TTpos) and disease-free survival.

This trial is expected to complete enrolling and result out after follow up in the next few years. This trial will establish the “clinical utility”— whether ctDNA status can be used to safely escalate or de-escalate adjuvant chemotherapy. This way only those patients that benefit from adjuvant chemotherapy will need to have it, thereby sparing everyone else from chemotherapy side effects. Those who are ctDNA positive and may need stronger chemotherapy would be able to get that as well.

Identification and Treatment of Micrometastatic Disease in Stage III Colon Cancer (ACT3)

NCT03803553

The Stand Up To Cancer ACT3 trial is an actively enrolling, multicenter, phase III clinical trial for stage III colon cancer patients. The trial is now open at Massachusetts General Hospital, Memorial Sloan Kettering Cancer Center, and Cornell.

Who is eligible? Stage III colon cancer patients who have completed surgery and adjuvant chemotherapy.

What is the goal of this study? After surgery and adjuvant chemotherapy, it is standard of care for patients to begin active surveillance. This study asks whether additional treatment (FOLFIRI or a biomarker-directed treatment) can reduce recurrence (versus active surveillance) in patients who are ctDNA positive after surgery and initial adjuvant chemotherapy.

What can patients expect? Participants are given a Guardant Reveal blood (ctDNA MRD) test to determine their ctDNA status (positive or negative).

Patients who are ctDNA negative will receive active surveillance, which includes observation and monitoring with imaging, tumor markers, and serial ctDNA monitoring. If ctDNA positive within the first year, they are randomized to one of the treatment arms as described below.

Patients who are ctDNA positive and have one of the tumor biomarkers will be assigned to the following treatment arms:

• HER2 overexpression/amplification: Trastuzumab + Pertuzumab (up to eight cycles)
• BRAF V600E: Encorafenib/Binimetinib/Cetuximab (up to twelve cycles)
• MSI-H/dMMR: Nivolumab (up to twelve cycles)

All other patients who are ctDNA positive are randomized to one of the following arms:

• Active surveillance (standard of care)
• FOLFIRI (up to twelve cycles)

What is being measured? The primary endpoints in this study are disease-free survival and clearance rate of ctDNA between ctDNA positive patients on active surveillance and those treated with FOLFIRI.

This is another trial whose results will inform the field about the clinical utility of ctDNA testing as well as what treatments may be beneficial for patients who are ctDNA positive after completing adjuvant treatment.

Trial of AMB-05X for Patients With ctDNA(+) Colorectal Cancer After Curative-intent Treatment

This is a small (15 participants), actively enrolling phase II trial. This trial is only open at MD Anderson Cancer Center in Houston, Texas.

Who is eligible? Patients with any stage colon or rectal cancer that have completed curative intent treatments, including adjuvant therapy, and are ctDNA positive with no clinically detectable disease.

What is the goal of this study? This study investigates the safety and efficacy of AMB-05X in CRC patients with MRD (defined by a positive ctDNA test and no clinically detectable disease).

What can patients expect? This is a single-arm trial, meaning that all participants receive the same treatment. All participants will receive AMB-05X (an anti-CSF1R monoclonal antibody) which is given intravenously.

What is being measured? The primary outcome measure is safety and adverse events.

The anti-CSF1R monoclonal antibody AMB-05X enhances T-cell infiltration and antitumor T-cell immune responses, potentially eliminating undetectable cancer cells in CRC patients who appear cancer-free. This might lower the odds of the cancer coming back, giving patients a better chance at staying healthy over the long term.

A phase II clinical trial comparing the efficacy of RO7198457 versus watchful waiting in patients with ctDNA-positive, resected stage II (high risk) and stage III colorectal cancer

(with a new cohort for stage IV patients with liver metastases that are NED after surgery)

NCT04486378

This is a phase II actively recruiting clinical trial for patients who have had surgery for high-risk stage II or stage III colorectal cancer. This is a multi-center trial with 118 locations across the United States and Europe.

Who is eligible? Stage II or III microsatellite stable (MSS) rectal or colon cancer patients with a positive ctDNA test after total tumor resection and that have completed at least three months of adjuvant chemotherapy. Additionally, there is a biomarker cohort for patients irrespective of post-surgical ctDNA status (positive or negative).

As of November 2024, this study also enrolls stage IV CRC patients with a positive ctDNA test after primary tumor resection and curative intent hepatectomy to treat liver metastases and have completed adjuvant chemotherapy.

All participants must have an R0 resection, confirmed by a pathology report, meaning that the tumor was completely resected with no microscopic evidence of cancer cells at the tumor site.

What is the goal of this study? This study evaluates the efficacy of RO7198457 (autogene cevumeran), an individualized mRNA neoantigen vaccine, to prevent cancer recurrence compared to watchful waiting (standard of care).

What can patients expect? Participants are randomized to receive either:

• RO7198457, a mRNA-based personalized vaccine (up to 15 doses given intravenously over 12 months)
• Watchful waiting, also referred to as active surveillance (standard of care)

A prior trial using this vaccine determined that the vaccine does generate tumor-specific immune responses, and it is safe: most adverse events (AE) were grade 1-2. AEs occurring in ≥ 20% of patients included infusion related reaction (IRR)/cytokine release syndrome (CRS), fatigue, nausea, and diarrhea. IRR/CRS were transient and reversible and presented primarily as Grade 1-2 chills and fever. No patients discontinued due to AE.

What is being measured? The primary endpoint is disease-free survival.

Recently reported results (Abs 29P at ESMO, June 2024) from the biomarker cohort of the trial show that RO7198457 (autogene cevumeran) successfully stimulated the immune system to produce T-cells that recognize specific cancer markers in the 11 patients in this group. These T-cells made up a notable portion of the patients’ immune cells after 8 doses, with up to 42% (median: 9%, range: 3-42%) of circulating CD8+ T-cell receptors being vaccine-specific in 8 patients. All the patients remained disease-free at median follow-up of 640 days (range: 602–779 days).

It’s notable that all the patients remain NED, given the nature of stage II and stage III high risk CRC, where recurrence rates can be significant. However, as this was the biomarker cohort, it does not directly prove that the vaccine prevented recurrence compared to no intervention. The main trial, which includes a watchful waiting arm for ctDNA positive patients for comparison, will provide clarity on efficacy.

Dose escalation and expansion study of TROP2 CAR engineered IL-15-transduced cord blood-derived NK cells in combination with cetuximab in patients with colorectal cancer (CRC) with minimal residual disease (MRD)

NCT06358430

This phase 1 active recruiting clinical trial explores a novel immunotherapy in CRC patients with MRD after surgery and standard adjuvant treatment.

Who is eligible? Colorectal cancer patients with MRD (defined as no evidence of radiological disease and a positive ctDNA test) following complete resection (surgery) and adjuvant therapy.

What is the goal of this study? This trial investigates the use of TROP2-CAR-NK cells, or TROP2 chimeric antigen receptor (CAR) engineered IL-15-transduced cord blood-derived natural killer (NK) cells (a type of adoptive cell therapy), combined with cetuximab (Erbitux®).

TROP2 is a protein often overexpressed in colorectal cancer. The therapy uses chimeric antigen receptor (CAR) technology to engineer NK cells—immune cells naturally equipped to kill cancer—to specifically recognize and attack TROP2-expressing cancer cells. The NK cells are modified with IL-15, a cytokine that boosts their survival and effectiveness, potentially making them better against residual cancer cells. The addition of standard of care cetuximab, that targets EGFR (another protein linked to CRC), may amplify the therapy’s impact.

The study aims to determine the highest and/or recommended dose of TROP2-CAR-NK cells in combination with cetuximab. It also seeks to assess the safety and tolerability of this combination therapy.

What can patients expect? This trial is a single-arm trial, meaning that all participants will receive the combination of TROP2-CAR-NK cells and cetuximab, both given intravenously.

What is being measured? Safety and adverse events are the primary focus. The study also measures circulating tumor DNA (ctDNA) clearance at 3 months, as an indicator of treatment effect.

If this therapy can eliminate hidden cancer cells, it could lower the chances of the disease returning, offering patients a better chance at long-term survival.

Some advice from patient advocates for people looking at MRD trials:

• Start your search early. Searching for trials and deciding on the right trial for you can take time. People interested in MRD trials should consider looking for them while they receive curative-intent treatment so that if they are ctDNA positive post-therapy, they can enroll in a MRD trial without much delay. There may also be opportunities for patients that are ctDNA negative to enroll in a clinical trial.
• Consider a liver MRI. It is important for patients that are ctDNA positive after curative-intent therapy to discuss getting a liver MRI with their healthcare provider before they decide to participate in a MRD trial (if a liver MRI is not part of the screening process for the trial). This is because an MRI may detect liver mets that a CT scan missed. Patients with a liver met may prefer to get local treatment, like surgery or ablation, to treat the lesion rather than enrolling in a clinical trial. Having this information can help patients make a more informed decision regarding their treatment.
• MRD trials may not be the best for everyone. By design, these trials may target patients with slow growing or indolent disease.

Stay Tuned

Our Clinical Trial Blog series unpacks important research trials, tips, and advice for our community. Be sure to subscribe to sign up with Fight CRC and join COLONTOWN’s online community to continue receiving the most relevant updates in the CRC world! You can also visit Fight CRC’s Clinical Trial Finder for more information on trials.

Overview

Are you curious about the latest scientific findings presented at the American Society of Clinical Oncology (ASCO) Gastrointestinal (GI) Cancers Symposium? Each year, patient advocates Maia and Manju outline relevant studies and advances of interest for the colorectal cancer community.

Highlights of GI ASCO

• Every year, researchers focused on gastrointestinal (GI) cancers, including colorectal cancer, present their work and latest findings at GI ASCO.
• Fight CRC research advocates attend the conference to learn more and report back to the community and share their insights.
• Fight CRC posts highlights from the annual meeting via blog posts and webinars to inform the community about promising clinical trials focused on treating colorectal cancer.

More Fight CRC Resources

• Clinical Trials
• Clinical Trial Blogs
• Biomarkers

2025

Amivantamab with or without chemotherapy in right-sided metastatic colorectal cancer: Updated results from OrigAMI-1, an open-label, phase 1b/2 study.

Abstract 197

The OrigAMI-1 trial (NCT05379595) is a phase 1b/2 study investigating amivantamab (a bi-specific antibody against EGFR and MET) by itself (monotherapy) and in combination with FOLFOX or FOLFIRI to treat advanced or metastatic CRC. Results were reported for right-sided metastatic CRC (mCRC) including primary tumors in the cecum, ascending colon, hepatic flexure, and transverse colon.

Participants: This trial enrolled patients with KRAS, NRAS, BRAF, and EFGR ectodomain wild-type unresectable or metastatic CRC without HER2 amplification. The trial enrolled both left- and right-sided CRC. However, only results from right-sided mCRC in Cohorts C, D, and E were reported, including the following:

• Cohort C: 23 patients with right-sided mCRC that received 2 or 3 prior lines of therapy (prior treatment with EGFR inhibitors was allowed)
• Cohort D (4 patients) and Cohort E (3 patients) with right-sided mCRC that received 1 prior line of therapy and no prior treatment with an EGFR inhibitor

Study design: Patients received amivantamab monotherapy (Cohort C) or amivantamab with FOLFOX (Cohort D) or FOLFIRI (Cohort E).

Results: Patients receiving amivantamab monotherapy (Cohort C) in third line+ (3L+) setting had an overall response rate (ORR) of 22% (5/23) and disease control rate (DCR) of 78% (18/23), with 1 patient having a complete response and 3 having an ongoing response. Patients receiving amivantamab in combination with FOLFOX (Cohort D) or FOLFIRI (Cohort E) in second line (2L) setting had an ORR of 43% (3/7) and a DCR of 86% (6/7), with 1 patient having an ongoing response.

Adverse events: Safety profile was consistent with what was expected.

Amivantamab monotherapy and amivantamab in combination with FOLFOX or FOLFIRI showed promising anti-tumor activity in this patient population. Ongoing phase 3 clinical trials using amivantamab include:

• OrigAMI-2 evaluates amivantamab versus cetuximab (both plus FOLFOX or FOLFIRI) as a first line (1L) treatment.
• OrigAMI-3 investigates amivantamab versus cetuximab or bevacizumab (all plus FOLFIRI) as a second line (2L) treatment.

BREAKWATER: Analysis of first-line encorafenib + cetuximab + chemotherapy in BRAF V600E-mutant metastatic colorectal cancer

Abstract 16

The BREAKWATER trial (NCT04607421) is a multi-center phase 3 clinical study comparing first line (1L) encorafenib (a BRAF inhibitor) and cetuximab (an EGFR inhibitor), together referred to as EC, with FOLFOX to standard of care (SOC) in patients with BRAF V600E-mutant metastatic CRC. Primary endpoints of this study include ORR and progression-free survival (PFS).

Participants: The study enrolled 479 patients (EC+FOLFOX = 236; SOC = 243) with previously untreated BRAF V600E-mutant metastatic CRC. Patient demographics were comparable between arms.

Study Design: The trial initially enrolled 1:1:1 to three arms: EC versus EC + FOLFOX versus SOC. However, the trial was amended to enroll 1:1 to two arms: EC + FOLFOX versus SOC.

Results: Primary analysis of ORR (assessed in the first 110 patients randomized to each arm) and an interim analysis of OS and safety was reported. The ORR was 60.9% (3 complete responses and 64 partial responses) in the EC + FOLFOX arm compared to 40% (2 complete responses and 42 partial responses) in the SOC arm. The EC + FOLFOX arm (n=67 patients) demonstrated an estimated median duration of response of 13.9 months (versus 11.1 months in the SOC arm [n=44 patients]) with double the number of patients with a duration of response ≥12 months compared to the SOC arm (15 and 5 patients, respectively).

Adverse Events: Adverse events were as expected in both arms.

Based on these results, EC + FOLFOX received FDA accelerated approval for treatment of patients with BRAF V600E-mutant mCRC and is considered the new standard of care in the first line setting for this population.

Neoadjuvant botensilimab (BOT) plus balstilimab (BAL) in resectable mismatch repair proficient (pMMR) and deficient (dMMR) colorectal cancer (CRC): NEST clinical trial update

Abstract 207

The NEST trial (NCT05571293) was a phase 2 study investigating the efficacy and safety of neoadjuvant (given before surgery) botensilimab (a Fc-enhanced, next-generation CTLA-4 inhibitor) plus balstilimab (a PD-1 inhibitor) (BOT/BAL) in patients with resectable pMMR/MSS and dMMR/MSI-H (CRC). The purpose of the study was to evaluate major pathologic response (MPR) rates.

Participants: The study enrolled 24 patients with pMMR/MSS (20) and dMMR/MSI-H (4) resectable CRC.

Study Design: This was a two-armed study:

• The NEST-1 arm (10 patients: 7 MSS and 3 MSI-H) received 1 dose of botensilimab and 2 doses of balstilimab two weeks apart.
• The NEST-2 arm (14 patients: 13 MSS and 1 MSI-H) received 1 dose of botensilimab and up to 4 doses of balstilimab two weeks apart.

The BOT/BAL treatment was followed by surgical intervention in both arms.

Results: High MPR rates were observed in both MSS and MSI-H CRC. MPR was defined as a ≥90% pathologic response (tumor regression). There was a 29% (2/7) MPR rate for MSS disease in the NEST-1 arm, which increased to 47% (7/14) with extended dosages in the NEST-2 arm. Notably, there was a 100% (4/4) MPR rate in patients with MSI-H CRC. No recurrences were reported.

Adverse events/side effects: Adverse events included instances of colitis or diarrhea and fever; however, there were no grade 4 adverse events or unresolved immune-mediated adverse events. Seven patients in the NEST-2 arm did not complete the balstilimab regimen. There were no delays in surgery due to immune-mediated adverse effects.

This trial suggests that the combination of BOT/BAL immunotherapies is a promising neoadjuvant therapy for CRC, particularly in achieving high MPR rates without serious adverse events. These findings could indicate a significant shift in the treatment strategies for CRC before surgery, especially for patients with difficult-to-treat pMMR/MSS and dMMR/MSI-H disease.

Another trial (NCT05608044) investigating the BOT/BAL combination in patients with metastatic MSS colorectal cancer with no liver metastases reported results during this ASCO GI 2025 conference (Abstract 23). Learn more about it on Fight CRC’s “Highlights from ASCO GI” webinar featured below.

Prognostic and predictive role of circulating tumor DNA (ctDNA) in stage III colon cancer treated with celecoxib: Findings from CALGB (Alliance)/SWOG 80702

Abstract LBA14

The CALGB/SWOG 80702 (NCT01150045) trial was a large phase III clinical study aimed at evaluating the efficacy of celecoxib (a nonsteroidal anti-inflammatory drug (NSAID)) in combination with FOLFOX chemotherapy in stage III colon cancer patients. It previously reported no significant improvement of disease-free survival (DFS) with the addition of celecoxib. This subgroup analysis explored whether circulating tumor DNA (ctDNA) status could guide adjuvant therapy decisions by identifying which patients may benefit from celecoxib.

Participants: A total of 2,524 patients with stage III colon adenocarcinoma previously treated with surgery were enrolled. For this subgroup analysis, ctDNA was measured after surgery but before the start of adjuvant therapy in 940 patients. Of these patients, 18.4% were ctDNA positive and 81.6% were ctDNA negative.

Study Design: Participants were randomized to receive either celecoxib or a placebo alongside FOLFOX chemotherapy for up to three years. These results are from a post hoc analysis (performed after the study is completed) that evaluated ctDNA after surgery as a biomarker for predicting treatment efficacy.

Results: The estimated 5-year OS rate was 91.5% in the ctDNA-negative population versus 52.6% in the ctDNA-positive population, which is consistent with findings from other trials. Celecoxib provided a significant disease-free survival (DFS) benefit in ctDNA-positive patients, with three-year DFS rates of 41.0% for celecoxib users compared to 22.6% for placebo. In contrast, ctDNA-negative patients exhibited similar DFS outcomes regardless of celecoxib or placebo treatment.

Adverse Events: Celecoxib was noted to be a feasible and tolerable addition with no significant increase in adverse outcomes over the placebo.

This study underscores the potential of ctDNA as a biomarker to tailor adjuvant therapy more effectively. Using ctDNA to identify patients who might benefit from adding celecoxib to the standard of care regimen could improve personalized treatment in some cases of colon cancer.

There is evidence from epidemiologic, preclinical and clinical studies suggesting that NSAIDs, like celecoxib, play a beneficial role in CRC chemoprevention, and potentially treatment. Three-year outcomes from the ALASCCA trial (NCT02647099), unveiled at the 2025 ASCO GI Cancer Symposium (LBA125), revealed that low-dose aspirin (an NSAID) usage in CRC patients with mutations in the PI3K pathway significantly reduced recurrence rates compared to a placebo. Discover more by watching Fight CRC’s Highlights from ASCO GI 2025 webinar featured below.

First results of nivolumab (NIVO) plus ipilimumab (IPI) vs NIVO monotherapy for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) from CheckMate 8HW

Abstract LBA143

The phase 3 CheckMate 8HW (NCT04008030) clinical trial evaluated the efficacy of immunotherapies nivolumab (an anti-PD-1 therapy) plus ipilimumab (a CTLA4 inhibitor) versus nivolumab monotherapy (or by itself) in patients with mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). The study aimed to assess progression-free survival (PFS) and other critical endpoints to establish an effective first-line treatment option for these patients.

Participants: The trial enrolled 703 patients who had histologically confirmed unresectable or metastatic colorectal cancer with MSI-H/dMMR status, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

Study Design: Participants were randomized into two arms: one receiving nivolumab with ipilimumab and the other receiving nivolumab monotherapy. The primary endpoints were PFS and overall response rates (ORR), with secondary endpoints including health-related quality of life (HRQOL) and safety.

Results: The nivolumab and ipilimumab combination significantly improved PFS compared to nivolumab alone, establishing it as the new standard of care for this patient population. The ORR in the combination arm was notably higher at 71% versus 58% in the monotherapy arm. Improvements in HRQOL were also observed in the combination arm.

Adverse Events: Treatment-related adverse effects were more frequent with the combination therapy, occurring in 81% of patients compared to 71% with monotherapy. Common adverse events included pruritus (itching), diarrhea, and hypothyroidism.

This trial highlights a promising advancement for the CRC community by addressing a need for effective first-line treatments for patients with MSI-H/dMMR mCRC. The use of nivolumab plus ipilimumab may offer a durable response and improved quality of life, marking a pivotal shift towards more personalized and efficacious cancer care strategies.

Discover more “Highlights from ASCO GI”

Discover more “Highlights from ASCO GI” by watching a recording of our recent webinar with oncologist Dr. Al Benson III (Northwestern University) and Fight CRC research advocate Michael Holtz! A few key points discussed during the webinar include:

• Overarching themes from the keynote presentation “Disrupting GI Oncology: Shattering Barriers with Inclusive Science” by Dr. Pamela Kunz, highlighting inclusive science and health equity.
• Data from the following five clinical trials:
  • BESPOKE CRC evaluated the ability of a ctDNA assay to inform treatment decisions in patients with stage II/III CRC.
  • In CALGB/SWOG 80702, researchers assessed whether ctDNA status after surgery could be used to determine which stage III colon cancer patients may benefit from adjuvant celecoxib.
  • ALASCCA looked at low-dose aspirin and recurrence rates in patients with CRC with PI3K pathway alterations.
  • BREAKWATER evaluates first-line encorafenib + cetuximab + chemotherapy in patients with BRAF V600E-mutant mCRC.
  • A study assessing botensilimab (BOT) with or without balstilimab (BAL) in patients with microsatellite stable (MSS) mCRC with no liver metastases.

2024

Maia: We learned much more about the role of circulating tumor DNA (ctDNA) tests in treating colorectal cancer at this meeting. I’m looking forward to Manju’s insights about that. From my end, I’d like to highlight four abstracts about research and clinical trials coming out from GI ASCO 2024 that are also important for the patient community.

NEST-1: Neoadjuvant botensilimab plus balstilimab in resectable mismatch repair proficient and deficient colorectal cancer

Abstract 117, Poster Bd H2; Pashtoon Murtaza Kasi, MD

The NEST-1 trial (NCT05571293) tested a new combination of drugs for patients with operable colorectal cancer (CRC): the immunotherapies botensilimab (a Fc-enhanced, next-generation CTLA-4 inhibitor) and balstilimab (a PD-1 inhibitor). This combination is also nicknamed “BOT/BAL.” The trial included 12 patients with the two types of colorectal cancer: nine with proficient mismatch repair/microsatellite stable (pMMR/MSS) and three with deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) CRC. These patients received one fixed dose of botensilimab plus two fixed doses of balstilimab two weeks apart. Following this second dose of balstilimab, and after a one-to-six week period, patients had surgery to remove the cancer.

The researchers reported that the combination of botensilimab and balstilimab was safe and well-tolerated by most patients, with only mild to moderate side effects (diarrhea, fever, chills, headache, fatigue, and rash). The combination also showed promising activity in both pMMR/MSS and dMMR/MSI-H cancers, with high tumor shrinkage and disappearance rates. A total of 67% (six out of nine) of patients with MSS experienced pathologic responses (defined as tumor reduction of at least 50%), and 100% (three out of three) of patients with MSI-H experienced major pathologic responses (defined as tumor reduction of at least 90%). The researchers also measured ctDNA levels in the blood before and after the treatment. They found that patients who had ctDNA before the treatment became negative after the treatment, which suggests that the combination eliminated most of the cancer cells in the body.

In conclusion, the neoadjuvant botensilimab and balstilimab combination was a promising strategy for patients with resectable colorectal cancer, especially for those with dMMR/MSI-H tumors. They also said that the trial showed that immunotherapy could work in pMMR/MSS tumors, which are usually resistant to this type of treatment, at least in this setting (neoadjuvant, before surgery).

Other ongoing clinical trials are testing this combination; you can perform a search in Fight CRC’s Trial Finder.

CheckMate 8HW: Nivolumab (NIVO) plus ipilimumab (IPI) vs. chemotherapy (chemo) as first-line (1L) treatment for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC)

Abstract LBA768; Thierry Andre, MD

The CheckMate 8HW trial (NCT04008030) compared two different treatments for patients with MSI-H, the type of advanced colorectal cancer with many mutations in their DNA, making the cancer cells more visible to the immune system and more resistant to some drugs. The study compared first-line treatment with the combination of nivolumab (OPDIVO®) and ipilimumab (YERVOY®), immunotherapies that target PD-1 and CTLA-4, respectively, to chemotherapy for metastatic disease.

The combination of nivolumab and ipilimumab resulted in a significant improvement in progression-free survival (PFS) compared to chemotherapy. The median PFS was not reached in the nivolumab plus ipilimumab group and was 5.9 months in the chemotherapy group. This shows a 79% reduction in the risk of disease progression or death. The PFS benefit was consistent across all pre-specified subgroups, including patients with KRAS or NRAS mutations, as well as patients with liver, lung, or peritoneal metastases when starting the trial.

The combination showed a safety profile that was consistent with previously reported data. The combination of immunotherapies was manageable with established protocols, and no new safety signals were identified. However, the toxicity of PD-1/CTLA-4 inhibitors combination therapy is significant (1%, two treatment-related deaths reported in the nivolumab and ipilimumab arm) and should be discussed when considering this option.

The take-home message: The combo of immunotherapies significantly reduced the risk of disease progression or death vs. chemotherapy in previously untreated patients with dMMR/MSI-H metastatic colorectal cancer (mCRC).

As Dr. Morris said during the Fight CRC 2024 GI ASCO recap webinar, it is too early to know if this combination of anti PD-1/CTLA-4 is superior to anti PD-1 monotherapy; we will await further updates from the CheckMate 8HW study.

Organ preservation in rectal cancer: What is at risk when offering watch-and-wait for a clinical complete response?

Abstract 7; Laura M. Fernandez, MD

In certain cases of locally advanced rectal cancer after neoadjuvant therapy, preserving the affected organ can serve as a viable alternative to total mesorectal excision (TME). For some patients who achieve a clinical complete response (cCR), a watch-and-wait strategy without immediate resection may be considered to preserve the quality of life with similar outcomes.

About 30% of patients who undergo the watch-and-wait approach develop local regrowth within three years of initiating watch-and-wait. While patients with this organ-preserving strategy have a low risk of developing distant metastases, those who develop local regrowth at any time during the surveillance program appear to represent a subgroup of patients who are at higher risk of developing distant metastases, according to a retrospective study presented at GI ASCO 2024.

The take-home message? Patients who opt for the watch-and-wait strategy and achieve a cCR should be offered active surveillance so they obtain the best oncological outcomes while maintaining a good quality of life. As expressed in the NCCN Guidelines for Patients® Rectal Cancer 2022: “This is only an option for carefully selected patients who agree to close surveillance programs. Surveillance involves digital rectal exams, proctoscopy, and MRI of the pelvis with a rectal cancer staging technique. The benefits and risks of taking a watch-and-wait approach versus having surgery are not fully known.”

Tumor genetics and sidedness predict outcomes

Abstract 207; Patrick M. Boland, MD

Oncology guidelines currently recommend using tumor sidedness to predict outcomes for first-line epidermal growth factor receptor (EGFR) monoclonal antibody therapy in mCRC – that is, when using drugs like cetuximab and panitumumab. For example, research has shown that right-sided tumors do worse with the anti-EGFR therapy cetuximab among patients with RAS wild-type disease when compared to anti-vascular endothelial growth factor (VEGF) therapies such as bevacizumab.

However, according to this recent study presented at GI ASCO 2024, this practice may need to be revised, as tumor sidedness might only be a surrogate marker for underlying tumor genomics.

Analyzing data from patients receiving first-line EGFR monoclonal antibody treatment for mCRC revealed that tumor genomics provided a significantly more accurate prediction of treatment outcomes than tumor sidedness.

Researchers found higher rates of KRAS, BRAF, and MAP2K1 alterations in right-sided tumors, and higher rates of APC and TP53 alterations in left-sided tumors.

Specific tumor gene mutations, such as RAS, BRAF, and APC mutations, are strongly associated with treatment response and overall survival, regardless of treatment received and sidedness.

Even if the findings require further validation in larger studies to inform practice guidelines, this research supports the transition from location-based treatment selection to a more personalized approach based on tumor genomics. Once again, know your biomarkers!

Manju: ctDNA has emerged as a prognostic biomarker in CRC, which may also be a predictive tool to guide treatment decisions in adjuvant and metastatic settings. Below, we review four abstracts with the more recent findings about this test.

AGITG DYNAMIC-Rectal study: Circulating tumor DNA analysis informing adjuvant chemotherapy in locally advanced rectal cancer

Abstract 12; Jeanne Tie, MD, FRACP, MBChB

This trial looked at the use of ctDNA to guide adjuvant chemo in a subset of stage III rectal cancer patients with tumors that have grown into many layers of the rectal wall.

This was a phase II trial for locally advanced rectal cancer patients (n=480) with T3-T4 disease and/or positive lymph nodes who got chemoradiation first, then surgery (total mesorectal excision (TME)) and were fit to get adjuvant chemotherapy.

Patients were randomly assigned 2:1 to ctDNA-guided treatment (where ctDNA status guided whether or not patients got chemo) or standard treatment. The ctDNA assay used was personalized and informed by the tumor. For the ctDNA-guided group, if ctDNA(+) at four and/or seven weeks after surgery, they got four months of oxaliplatin or 5FU-based chemo. If ctDNA(-), patients did not get any chemo if there was no lymph node involvement but got clinician’s choice chemo if node-positive. The primary endpoint was adjuvant chemo use.

This study stopped early due to COVID-19 and the adoption of total neoadjuvant treatment (TNT). The results presented at GI ASCO 2024 were based on 230 patients enrolled, and the median follow-up was 37 months.

CtDNA analysis was successful in 97% of patients who received ctDNA-guided treatment, and 28% were found to be ctDNA(+). In comparison to the standard management arm, the use of adjuvant chemotherapy was much less in the ctDNA-guided arm, with only 46% of patients receiving it. The three-year recurrence-free survival for ctDNA-guided was 76% and 82% for the standard management arm.

The authors concluded that a ctDNA-guided approach after neoadjuvant chemoRT and surgery was associated with lower chemo use.

BESPOKE CRC study: Circulating tumor DNA (ctDNA) for informing adjuvant chemotherapy (ACT) in stage II/III colorectal cancer (CRC)

Abstract 9; Pashtoon Murtaza Kasi, MD

These are the first results of the BESPOKE CRC observational trial (NCT04264702) (N=350), looking at the ability of a tumor-informed ctDNA assay (Signatera™) to guide adjuvant chemotherapy treatment decisions in stage II/III CRC patients.

These results are from the first 154 stage II and 196 stage III patients who had the Signatera™ minimal residual disease (MRD) ctDNA test done and had a median follow-up of 24.8 months. After curative surgery, 232 patients got adjuvant chemotherapy, and 118 had observation without chemotherapy. ctDNA results at the post-surgery MRD time point were available for 295 patients; 15.6% were ctDNA(+), including 6.9% of stage II and 22.4% of stage III patients. CtDNA(+) patients had higher disease recurrence rates, as shown by significantly lower median disease-free survival (DFS). In the MRD ctDNA(+) group, adjuvant chemotherapy reduced recurrence, but no benefit was seen in ctDNA(-) patients.

From a patient perspective, testing for ctDNA was welcomed by those participating in this study: 73% of patients said that ctDNA results reduced anxiety about recurrence, while 87% said they felt they were receiving the proper treatment knowing their ctDNA results.

GALAXY study: Circulating tumor DNA (ctDNA) dynamics in patients with colorectal cancer (CRC) with molecular residual disease

Abstract 6; Hiroki Yukami, MD

This abstract covers the analysis and correlation of ctDNA dynamics with outcomes in patients with stage II-IV CRC after curative-intent surgery from the GALAXY study.

The Signatera™ assay detected and quantified ctDNA in serial plasma samples collected at one, three, six, nine, 12, 18, and 24 months post-surgery until recurrence. Post curative-intent surgery, patients had either adjuvant chemotherapy (N=1,000) or observation (N=1,518). The primary endpoint was disease-free survival (DFS).

Of the 3,034 CRC patients enrolled in the GALAXY study, 2,518 met the inclusion criteria and were analyzed in this sub-study. After surgery, 309 (14.8%) were ctDNA(+) and, of those, 181 received adjuvant chemotherapy and 72.9% (132/181) had ctDNA clearance. Around 54% of patients had sustained ctDNA clearance, while 46% eventually tested positive for ctDNA again. Patients with sustained clearance had significantly better outcomes than those with transient ctDNA clearance.

Both the BESPOKE and GALAXY results show that ctDNA MRD results and ctDNA dynamics in response to adjuvant chemo were highly predictive of patient outcomes.

NRG-GI005 (COBRA) phase II/III study: Phase II results of circulating tumor DNA as a predictive biomarker in adjuvant chemotherapy in patients with stage II colon cancer

Abstract 5; Van Morris, MD

The COBRA trial (NCT04068103) looked at low-risk stage II colon cancer to identify patients who were ctDNA(+) and to see if they may benefit from adjuvant chemotherapy.

In this prospective phase II/III clinical trial, low-risk stage II colon cancer patients, as determined by the treating oncologist to not need adjuvant chemotherapy, were randomized 1:1 to two arms. Arm A is the standard-of-care/observation arm, while Arm B is the ctDNA-directed therapy arm.

Blood was analyzed after surgery for ctDNA using the Guardant LUNAR assay, a non-tumor-informed assay that includes genomic and epigenetic markers. Patients in Arm B who were ctDNA(+) were treated with six months of adjuvant CAPOX or FOLFOX.

Six hundred thirty-five (635) patients were randomized into Arm A (318) and Arm B (317). In the first 16 ctDNA(+) patients, clearance of ctDNA after six months was observed in three out of seven patients (43%), in the control arm with no adjuvant chemotherapy, and one out of nine patients (11%) in the experimental arm after adjuvant chemotherapy. This was unexpected, so the study was prematurely stopped. There were no unanticipated toxicities in those treated with chemotherapy.

2023

Maia:

Results from a phase 1a/1b study of botensilimab (BOT), a novel innate/adaptive immune activator, plus balstilimab (BAL; anti-PD-1 antibody) in metastatic heavily pretreated microsatellite stable colorectal cancer (MSS CRC)

Abstract #LBA8; Poster Bd #A1; Anthony B. El-Khoueiry

This year’s conference brought to our community some encouraging news from the combination of two immunotherapy drugs for metastatic microsatellite stable colorectal cancer (MSS CRC). The combo treatment with botensilimab and balstilimab (BOT + BAL) was received by 70 patients in this trial. Botensilimab is a next-generation, Fc-enhanced, CTLA-4 inhibitor, and balstilimab is a PD-1 inhibitor; that is, they are two different types of immunotherapy. The administration of these two immunotherapies resulted in objective response rate (ORR) at 23%, disease control rate at 76%, progression-free survival (PFS) 4.1 months, and the median overall survival has not been reached. The estimated 12-month overall survival at 63% is better than the current standard of care.

It is interesting to note that patients had received a median of four prior lines of therapy, and 59% had RAS mutations. Prior immunotherapy was allowed in this trial.

Most patients (91%) reported immune-related adverse events (irAEs). The most common were diarrhea/colitis (43%) and fatigue (34%). The most common grade 3 irAEs were diarrhea/colitis (20%), fatigue (4%), and pyrexia (raised body temperature) (4%).

These are results from expanded phase 1a/1b study, NCT03860272; a phase 2 trial of this combination is currently enrolling patients (NCT05608044), and a phase 3 trial is planned.

BREAKWATER safety lead-in (SLI): Encorafenib (E) + cetuximab (C) + chemotherapy for BRAFV600E metastatic colorectal cancer (mCRC)

Abstract # 119; Poster Bd #F16; Scott Kopetz

For the treatment of BRAF V600E-mutant metastatic colorectal cancer (mCRC), data from the safety lead-in (SLI) portion of phase 3 BREAKWATER study show that the combination of encorafenib (Braftovi®) with cetuximab (Erbitux®) and chemotherapy was well-tolerated and resulted in anti-tumor responses in patients receiving this combination as early therapy.

The combination encorafenib + cetuximab is already approved, since 2021, for BRAF+ patients who already received other treatments for mCRC, based on results from the BEACON phase 3 trial. This phase 3 BREAKWATER study (NCT04607421) aims to determine what treatment works better for BRAF+ MSS mCRC patients who had not received treatment yet: encorafenib plus cetuximab; encorafenib plus cetuximab with chemotherapy; or chemotherapy alone.

Results from both combinations (encorafenib/cetuximab with FOLFOX or FOLFIRI), for both groups of patients (receiving it first or second line) show a high degree of activity and compared favorably with historic data for these patients with BRAF V600E-mutant mCRC, who generally have lower response rates with cytotoxic chemotherapy. Side effects were less in the FOLFIRI combination than in the FOLFOX one.

SUNLIGHT: Trifluridine/tipiracil plus bevacizumab for third-line treatment of refractory metastatic colorectal cancer

Abstract #4; Oral Abstract Session; Josep Tabernero

The phase 3 randomized SUNLIGHT (NCT04737187) study tested the combination of trifluridine/tipiracil (Lonsurf®, TAS-102) + bevacizumab (Avastin®) for third-line treatment of refractory metastatic colorectal cancer (mCRC) versus the standard of care, consisting in receiving Lonsurf alone.

The results were “statistically significant and clinically meaningful” improved overall survival (OS) and disease control rate (DCR) when bevacizumab (BEV) was added to trifluridine/tipiracil (FTD/TPI): There was a 3.3 months improvement in OS (10.8 months in the treatment arm versus 7.5 months in the control arm).

The study evaluated 492 patients with histologically confirmed mCRC who had been previously treated with fluoropyrimidine, irinotecan, oxaliplatin, an anti-VEGF monoclonal antibody (not necessarily bevacizumab), and/or an anti-EGFR monoclonal antibody in those patients whose tumor harbored a RAS mutation. All subgroups benefited from the addition of bevacizumab; the greater benefit from the combination was seen in those patients who had not been previously treated with bevacizumab.

Regarding quality-of-life characteristics, the median time to deterioration in global health status in the treatment arm was 8.5 months in the experimental arm versus 4.7 months in the control arm. These results are practice changing, and the combination of TAS-102 with bevacizumab may represent a new option in standard of care for the treatment of patients with refractory mCRC with disease progression after two lines of therapy.

Phase II evaluation of combination immunotherapy with CV301, N-803, bintrafusp alfa, and M9241 in patients with advanced small bowel and colorectal cancers

Abstract #116; Poster Bd #F13; Danielle M. Pastor

At GI ASCO 2023, we also learned about some preliminary but encouraging results from an ongoing study at the National Institutes of Health (NIH). It is a phase 2 trial that evaluates combination immunotherapy with CV301 (a therapeutic vaccine), N-803 (IL-15; a superagonist), bintrafusp alfa (M7824; a PD-L1 and TGF-beta trap “bifunctional drug), and M9241 (NHS-IL12; a tumor targeted immunocytokine) in patients with advanced small bowel and colorectal MSS cancers (NCT04491955).

Thirty patients (two small intestinal, 17 colon, and 11 rectal) were treated. In this trial, they received treatment with three of those immunotherapies (12 patients) or with the four agents (18 patients). The patients had received at least two prior lines of therapy previously to participate in the trial.

Triple therapy resulted in disease reduction in two patients; quadruple therapy resulted in disease reduction in two patients. Median overall survival (OS) for triple and quadruple therapy have not been reached, with 12-month survival being 66.7% (for triple therapy), and 77.2% (for quadruple therapy). Grade 3 treatment-related adverse effects (TRAEs) occurred in eight patients (26.7%); no grade 4 or 5 TRAEs occurred.

This means that preliminary clinical activity was observed in patients with advanced MSS/pMMR small bowel or CRC with these drugs, which had manageable safety profiles. The median OS was promising, as compared to historical median survivals of six to seven months following receipt of multiple lines of therapy.

Other trials of interest

A couple of trials that we have been following for a while presented results and, even when there were no tumor responses, it is important to learn about them.

ILOC: Durvalumab and tremelimumab plus local tumor ablation in patients with metastatic colorectal cancer with unresectable liver metastases

Abstract #141; Poster Bd #G19; Jenny Seligmann

Synergism of Immunomodulation and Tumor Ablation (ILOC) is a now-completed multicenter European trial (NCT03101475) that used the immunotherapies durvalumab and tremelimumab along with local tumor ablation (radiofrequency ablation (RFA) or stereotactic body radiotherapy therapy (SBRT)) in patients with mCRC unresectable liver metastases. In this study, the addition of immunotherapy did not result in responses in other lesions than those that were treated locally, with ablation (with RFA or SBRT). This means that further strategies are required to improve response to immunotherapy in these cases.

OBERTO-201: PolyPEPI1018 vaccine as an add-on immunotherapy to TAS-102

Abstract #147; Poster Bd #H6; Joleen M. Hubbard

The trial OBERTO-201 (NCT05130060) investigates the combination of a cancer vaccine (PolyPEPI1018) with Lonsurf® (TAS-102) in advanced MSS mCRC.

The results show that the combination was well-tolerated, with few grade 3 adverse events beyond what is expected with Lonsurf monotherapy.

Even if no objective tumor responses could be detected, the vaccine PolyPEPI1018 induced immunological responses at both peripheral and tumor level; testing post-treatment showed that patients with better progression-free survival had robust vaccine-specific T cell responses to it.

Manju:

Organ preservation and total neoadjuvant therapy for rectal cancer: Investigating long-course chemoradiation versus short-course radiation therapy

Abstract #10; Rapid poster abstract session; Paul Bernard Romesser

This study looked at the feasibility of organ preservation between short course radiation (SCRT) and long-course chemoradiation (LCRT) as part of total neoadjuvant therapy (TNT) for locally advanced rectal cancer, where the disease has spread to nearby lymph nodes. This a retrospective study of 563 patients who received TNT, 76 in SCRT and 256 in LCRT group.

The rates of clinical complete responses were 46% in both groups, but the median follow-up period was longer in the LCRT group. Despite identical clinical complete responses in both groups for the entire cohort, two-year organ preservation rates were 29% in the SCRT group and 40% in the LCRT group. Also, in those who followed watch and wait, the two-year organ preservation rates were 88% in the LCRT group compared to 67% in the SCRT group.

So overall, it looks like if the goal is organ preservation, LCRT seems to be the best bet. While if organ preservation isn’t the goal, and patients undergo surgery, then short course may seem attractive with similar oncologic outcomes when compared to LCRT.

Analysis of the impact of eliminating bolus 5-fluorouracil in metastatic colorectal cancer

Abstract #59; Poster Bd #C14; Chengwei Peng

It is common practice for 5-FU to be given as a bolus followed by an infusion as part of treatment for stage IV colorectal cancer (CRC). The bolus dose increases side effects and is commonly not given in patients with poor functional status or those who have other serious health conditions, but its impact on treatment outcomes are not clear.

This study looks at whether not giving the 5-FU bolus is associated with a difference in OS. In this retrospective study of 9741 patients with stage IV CRC who got 5-FU-based chemo as first line: Everyone received a 5-FU infusion, and 81% also got a 5-FU bolus. The median follow-up time was for 19 months. In different analyses (univariable and multivariable), there was no association between the use of bolus 5-FU and overall survival.

The results from this large multicenter cohort study show that, after adjusting for patient and treatment factors, 5-FU bolus was not associated with an OS benefit in patients with mCRC. This suggests that getting a 5-FU bolus does not appear to add efficacy to chemotherapy containing infusional 5-FU.

PARADIGM biomarker study: Negative hyperselection of patients with RAS wild-type metastatic colorectal cancer for panitumumab

Abstract #11; Poster Bd #A4; Kohei Shitara

The phase 3 PARADIGM study was positive and showed that adding first line EGFR-inhibitor (Panitumumab) with mFOLFOX6 was superior (median overall survival (OS) 37.9 months versus 34.3 months) to mFOLFOX6 + bevacizumab in left-sided and RAS wild-type (WT, unmutated) metastatic colorectal cancer (mCRC).

What they found is that overall in the hyperselected population with no alterations in the genes tested, OS was longer with panitumumab than with bev (41.3 months versus 34.4 months). In both the right-sided and left-sided population with alterations in the genes tested, bev addition seemed to result in better OS.

Regorafenib, ipilimumab, and nivolumab (RIN) in chemotherapy-resistant MSS metastatic colorectal cancer (mCRC)

Abstract #110; Poster Bd. #F7; Marwan Fakih

This poster shows efficacy data at the recommended phase 2 dose (RP2D) of regorafenib (R), ipilimumab (I), and nivolumab (N) (RIN) in microsatellite stable (MSS) metastatic colorectal cancer (mCRC).

39 patients – 29 on the RP2D (seven with liver mets) and 10 (three with liver mets) at the amended 40 mg to 80 mg cohort were enrolled. No significant clinical activity was noted in patients with liver mets (overall response rate (ORR) = 0%, median progression-free survival (mPFS) = two months. The ORR was 36% in patients with no liver mets, and the mPFS was five months.

RIN (80/1/240) has substantial activity in MSS mCRC patients with no liver mets. These data suggest that a starting regorafenib dose of 80 mg is important in priming the immune response to RIN. The RP2D of 80/1/240 mg is recommended for further investigation in mCRC with no liver mets.

Clinical trial information: NCT04362839.

Stay Tuned

Once a month, Maia Walker and Manju George spend time unpacking important research trials, tips, and advice for our community. Be sure to subscribe to sign up with Fight CRC and join COLONTOWN’s online community to continue receiving the most relevant updates in the CRC world! You can also follow Maia (@sassycell) and Manju (@manjuggm) to stay updated on research and trials and visit ClinicalTrials.gov or Fight CRC’s Clinical Trial Finder for more information on trials.

In this blog, we take a deep dive into the Multicenter Phase 1b/2 Study of Adagrasib, Cetuximab, and Cemiplimab for Metastatic Colorectal Cancer Harboring KRAS G12C Mutations (NCT06412198) clinical trial alongside Drs. Christine Parseghian and Bennett Caughey. Special thanks to Drs. Christine Parseghian and Bennett Caughey for their contributions to this blog and to colorectal cancer research!

Who: Patients with stage IV, metastatic colorectal cancer with KRAS G12C mutation

• What: A phase 1b/2 clinical trial investigating whether adding immunotherapy (cemiplimab) to standard of care (adagrasib plus cetuximab) improves response rate and duration of response
• When: Currently recruiting
• Where: Houston, Texas (MD Anderson Cancer Center) and Boston, Massachusetts (Massachusetts General Hospital Cancer Center)
• Why: To improve treatment outcomes for patients with mCRC harboring a KRAS G12C mutation

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What is the primary objective of this trial?

The primary goal of this trial is to answer this question:
Does adding immunotherapy (cemiplimab (Libtayo®), an anti-PD-1 therapy) to standard of care (adagrasib (Krazati®), a KRAS G12C inhibitor, and cetuximab (Erbitux®), an anti-EGFR therapy) for patients with KRAS G12C mutated metastatic CRC (mCRC) significantly improve response rate? The secondary objective is to estimate the duration of response, progression-free survival, and overall survival. The study also aims to estimate the safety and tolerability of the combination.

What is the rationale for this study?

According to Dr. Parseghian, KRAS G12C mutations occur in approximately 4% of all patients with metastatic colorectal cancer (mCRC) and are associated with poor survival. Dr. Parseghian points to three main observations that led to the development of the treatment strategy used in this trial.

1. Analysis of 94 previously treated KRAS G12C mCRC patients who received adagrasib and cetuximab in the KRYSTAL-1 trial revealed an overall response rate of 34% and a disease control rate of 85% at 12 months. However, the median duration of response was only 7 months, and median survival was 16 months. These results led to the Food and Drug Administration (FDA) granting accelerated approval (June 2024) to adagrasib (KRAS G12C inhibitor) plus cetuximab (anti-EGFR therapy) for adults with KRAS G12C-mutated locally advanced or mCRC who have received previous treatment with chemotherapy. The adagrasib and cetuximab combination is the current standard of care. However, the fact that most patients with KRAS G12C mCRC developed early progression highlights the ongoing unmet need for this population.
2. Preclinical studies in mutant KRAS G12C tumor models show that adagrasib enhances the potential for tumor cells to present antigens and reconditions the tumor microenvironment through changes in the proportions of key cell populations, both of which are predicted to increase susceptibility to immune checkpoint inhibition.
3. In the phase I SWOG 2107 trial, a significant improvement in overall response rate and durability was seen with a similar strategy using combined immunotherapy (anti-PD-1 therapy) plus encorafenib (BRAF inhibitor) and cetuximab (anti-EGFR therapy) in patients with BRAF V600E mutations.

These observations suggest the combination of adagrasib plus cetuximab (currently the standard of care) with a PD-1/PD-L1 inhibitor may improve response rates and duration of response compared to the current standard of care alone.

Who is eligible to participate in this trial?

• Patients must have mCRC.
• The cancer must have a KRAS G12C mutation. Other KRAS mutations are unfortunately not eligible.
• Patients must have received at least 1 prior treatment. Patients must not have received previous targeted treatment against KRAS or EGFR (such as standard-of-care adagrasib and cetuximab or sotorasib and panitumumab), or any kind of immunotherapy before starting the trial.
• Because the trial uses immunotherapy, patients cannot have a severe autoimmune condition. However, patients are encouraged to reach out to inquire whether their specific condition is disqualifying.

What should patients expect when participating in this trial?

Prior to starting therapy, patients will undergo a screening process including a clinic visit, blood work, an electrocardiogram (ECG), and imaging to ensure they are eligible for the trial.

If eligible, patients will then start on the treatment as soon as possible. This trial is a single arm study where all patients receive the same 3 medicines. One medicine, adagrasib, is a pill that will be taken twice a day, every day. The other two medicines are IV infusions and will be given in the infusion center. The cetuximab will be given every 2 weeks while the cemiplimab will be given every 3 weeks. This results in a 6-week cycle. IV infusion will occur on weeks 1, 3, 4, and 5, while weeks 2 and 6 are a break from IV treatment.

In addition, patients will be asked to undergo a biopsy before starting treatment and another biopsy 2 weeks into treatment, if safe to do so.

Is there anything else patients should know about this trial?

We asked Drs. Parseghian and Caughey what else interested patients should know about this trial. Here are their thoughts:

Dr. Parseghian: “I would encourage patients with metastatic CRC to ensure molecular testing for KRAS G12C is completed early in their disease assessment, and to present to MD Anderson or MGH as soon as a KRAS G12C mutation is identified. Patients will need to have had at least one prior line of therapy for metastatic CRC; however, if they have received prior KRAS G12C directed therapy, they would be ineligible for this trial.”

Dr. Caughey: “This trial takes a good, standard therapy for KRAS G12C and adds immune therapy to it. That means that this trial is giving a treatment a KRAS G12C patient would get anyway, plus something extra that may make it work better and for longer.”

Acknowledgements

Special thanks to Drs. Christine Parseghian and Bennett Caughey for their contributions to this blog and to colorectal cancer research.

Dr. Bennett Caughey is a GI medical oncologist at Mass General Brigham Cancer Center. He is a clinical investigator with a focus on colorectal and anal cancers. Dr. Caughey has a particular interest in the applications of molecular testing (e.g., DNA sequencing), such as which tests to use in each situation and how to interpret ambiguous results. He aims to open clinical trials using targeted therapies based on the specific changes in the DNA of a cancer.

Dr. Christine Parseghian is a GI Medical Oncologist at MD Anderson Cancer Center. She is a clinical scientist with a focus in colorectal cancer, particularly KRAS G12C mutated colorectal cancer, and mechanisms of acquired resistance to anti-EGFR directed therapy. Dr. Parseghian runs several clinical trials in this setting and is actively involved in translational research in this space.

Stay Tuned

Once a month, Maia Walker and Manju George spend time unpacking important research trials, tips, and advice for our community. Be sure to subscribe to sign up with Fight CRC and join COLONTOWN’s online community to continue receiving the most relevant updates in the CRC world! You can also follow Maia (@sassycell) and Manju (@manjuggm) to stay updated on research and trials and visit ClinicalTrials.gov or Fight CRC’s Clinical Trial Finder for more information on trials.