Overview

Are you curious about the latest scientific findings presented at the European Society for Medical Oncology (ESMO) Congress? Each year, patient advocates Maia and Manju outline relevant studies and advances of interest for the colorectal cancer community.

Highlights of ESMO GI Congress

• When: Takes place in July
• Where: Barcelona
• Who: Researchers focused on GI cancers from around the world present their work and latest findings.
• What: Fight CRC posts updates to inform the community about promising clinical trials for colorectal cancer.

Resources

More Fight CRC Resources:

• About Clinical Trials
• COLONTOWN Clinical Trial University

2024

Neoadjuvant Immunotherapy for dMMR/MSI-H Colon Cancer

Patients with microsatellite instability (MSI)/mismatch repair deficient (dMMR) colon cancer who undergo surgery may benefit from receiving neoadjuvant immunotherapy.

Standard-of-care chemotherapy offers limited benefit to patients with MSI-H/dMMR colon cancer, with recurrence rates up to 40% in individuals with stage III disease. Clinical trials such as the three highlighted here are investigating treatment strategies to improve these patient outcomes.

Abstract LBA24: Neoadjuvant immunotherapy in locally advanced MMR-deficient colon cancer: 3-year disease-free survival from NICHE-2

Summary: The NICHE-2 phase II, nonrandomized, multicenter trial has previously reported reaching one of its primary endpoints and one secondary endpoint: safety and pathologic response rate, respectively. The pathologic response rate was 98%, including 95% major pathologic response (≤ 10% residual viable tumor, MPR) and 68% pathologic complete response (pCR). The results for the other primary endpoint, 3-year disease-free survival (DFS), were reported at ESMO 2024.

Participants: 112 patients with nonmetastatic, stage III, previously untreated dMMR colon adenocarcinoma.

Study Design: Participants received ipilimumab and nivolumab (immunotherapy) on day 1 and only nivolumab two weeks later, followed by surgery within 6 weeks. Circulating tumor DNA (ctDNA) was analyzed at baseline, day 15, pre-surgery and 3 weeks post-surgery (minimal residual disease (MRD) timepoints).

Results: The 3-year DFS was 100% in 111 patients, meaning that all patients were alive and had no disease recurrences at the time of follow-up after surgery. In 108 patients with available samples, baseline ctDNA was detected (positive) in 92%. All patients were ctDNA negative at the MRD timepoint.

Safety: As reported previously, 61% of patients experienced an immune-related adverse event of any grade, but they were grade 3 or 4 (severe or life-threatening, respectively) in only four patients. Two patients had an immune-related adverse event leading to a delay in surgery of at least 2 weeks.

Results from two additional clinical trials presented at ESMO 2024 (below) similarly supported a benefit of neoadjuvant immunotherapy for dMMR/MSI-H colon cancer patients undergoing surgery.

Abstract 5030: Neoadjuvant nivolumab (nivo) plus relatlimab (rela) in MMR-deficient colon cancer: Results of the NICHE-3 study

Summary: In the phase II NICHE-3 study, patients with locally advanced resectable dMMR colon cancer received two doses of nivolumab and relatlimab (immune checkpoint inhibitors) before surgery. The pathological response (≤50% residual viable tumor) rate was 97% in 59 patients who had undergone surgery, which included a MPR rate of 92% and a pCR rate of 68%.

Abstract 5040: IMHOTEP Phase II trial of neoadjuvant pembrolizumab in dMMR/MSI-H tumors: Results of colorectal cancer cohort

Summary: IMHOTEP phase II trial patients with localized resectable dMMR/MSI colon or rectal cancer received one or two cycles of pembrolizumab (immunotherapy) before and after surgery for 1 year. pCR was obtained in 54% of the patients who had surgery. pCR rate increased with the number of pembrolizumab cycles, from 47% with 1 to 68% with 2 cycles. This is the first study showing that pCR rate increases with the number of neoadjuvant immunotherapy cycles. Future studies will be needed to determine the optimal number of cycles in this treatment setting.

Organ Preservation in Rectal Cancer

Active surveillance without surgery after successful chemotherapy plus radiation treatment may allow for rectum preservation in rectal cancer patients.

Patients with microsatellite stable (MSS)/mismatch repair proficient (pMMR) locally advanced rectal cancer (LARC) usually receive total neoadjuvant treatment (TNT) followed by surgery as standard of care. Clinical trials such as the one highlighted below aim to determine whether surgery can be safely avoided in patients with a complete clinical response (cCR) to initial therapy.

Abstract 5090: Total neoadjuvant treatment (TNT) with non-operative management (NOM) for proficient mismatch repair locally advanced rectal cancer (pMMR LARC): First results of NO-CUT trial

Summary: NO-CUT is an Italian phase II, multicenter, single arm trial.

Participants: 180 patients with stage II or stage III MSS/pMMR rectal cancer

Study Design: Patients received TNT consisting of chemotherapy (4 CAPOX cycles) followed by long-course chemoradiotherapy. After TNT, patients were assigned to surgery or non-operative management (intensive follow-up) groups based on cCR parameters.

Results: 26% of patients achieved cCR after TNT and proceeded with non-operative management. The distant relapse-free survival (DRFS) at 30 months was 96% in the non-operative management (NOM) and 74% in the rectal surgery groups. Local regrowth occurred in 15% of NOM and 9% of surgery groups; all local regrowth patients underwent rescue surgery, which in 42% (3/7) of cases was sphincter-preserving. After TNT, positive ctDNA (ctDNA+) was significantly associated with incomplete response and worse DRFS. After surgery, patients with ctDNA+ had a significant increased risk for progression.

Safety: The safety profile was consistent with expectations for TNT, with manageable side effects. Some patients experienced local regrowth, but these cases were managed effectively with subsequent treatments. 12 deaths were reported (1 adverse event-, 9 tumor-, and 2 other causes-related).

As shown in this trial and in the randomized, phase II OPRA trial in the United States, non-operative management following cCR to TNT did not negatively affect the risk of distant relapse and benefited organ preservation for patients with MSS/pMMR LARC. These results may have important implications for the future management of this patient population.

Immunotherapy for MSS/pMMR Metastatic CRC

Preliminary results suggest addition of immunotherapy may be effective in a subset of patients with MSS/pMMR metastatic colorectal cancer.

Immunotherapy is generally considered ineffective in patients with MSS/pMMR mCRC. The clinical trial highlighted below is studying whether the addition of immunotherapy to standard of care may improve outcomes in a subset of patients.

Abstract 5020: Pembrolizumab in combination with CAPOX and bevacizumab in patients with microsatellite stable metastatic colorectal cancer and a high immune infiltrate: Preliminary results of FFCD 1703 POCHI trial

Summary: POCHI is a phase II, multicenter, single arm trial to determine progression-free survival (PFS) at 10 months after the start of treatment.

Participants: 30 patients with previously untreated, stage IV (metastatic), MSS/pMMR colorectal cancer with high immune infiltrate (high numbers of immune cells in a tumor) determined using Immunoscore® and/or TuLIS score.

Study Design: Patients received pembrolizumab, in combination with CAPOX and bevacizumab, every 3 weeks. The median duration of treatment was 9.5 months.

Results: At the time of interim analysis, the disease control rate (DCR) was 100% and the overall response rate (ORR) was 74%, with 17% (5/30) of patients having a complete response. The 12-month PFS rate was 51% and the 2-year overall survival (OS) rate was 80%.

Safety: The side effect profile was as expected for these drugs. 70% of patients had at least one grade 3+ adverse event.

EGFR Inhibitor Rechallenge

Patients negative for RAS, BRAF, and EGFR mutations may benefit from rechallenge with EGFR inhibitors.

Patients with RAS wildtype metastatic CRC (mCRC) are often treated with chemotherapy in combination with an EGFR inhibitor in the first line setting. There is preliminary evidence suggesting that patients who progress may benefit from rechallenge (reintroduction) with EGFR inhibitors in later lines of treatment.

Abstract 511MO: Third line rechallenge with cetuximab (Cet) and irinotecan in circulating tumor DNA (ctDNA) selected metastatic colorectal cancer (mCRC) patients: The randomized phase II CITRIC trial

Summary: The CITRIC trial is a multicenter, randomized, open label, phase II study.

Participants: Patients with MSS, RAS wildtype (no mutations) mCRC who benefited from an EGFR inhibitor (e.g., cetuximab) in the first line (1L) setting, but then progressed on a second line (2L) chemotherapy (without EGFR inhibitors) were eligible. 58 eligible patients were negative for RAS, BRAF V600E, and EGFR extracellular domain (ECD) mutations by liquid biopsy and enrolled.

Study Design: Enrolled patients were randomly assigned to either cetuximab (an EGFR inhibitor) and irinotecan (chemotherapy) or investigator’s choice of therapy (excluding EGFR inhibitors) as a third line (3L) therapy.

Results: Patients rechallenged with EGFR inhibitor cetuximab, in combination with irinotecan had better ORR (12% vs 0% on investigator’s choice) and DCR (74% vs 44% on investigator’s choice). The median PFS was 4.4 months for those rechallenged compared to 2.2 months on investigator’s choice.

2023

The abstracts mentioned can be found by searching the Abstract number or the trial name in ESMO 2023

PEGASUS

The phase II PEGASUS trial shows results of using the Guardant Reveal ctDNA blood test to guide adjuvant treatment of patients with high-risk stage II or stage III colon cancer to reduce toxicity from chemotherapy and improve the response to standard chemotherapy regimens.

In this trial, which included high risk stage II and stage III colon cancer patients, post-surgical treatment if ctDNA (+) was 3 months capecitabine + oxaliplatin or 6 months of capecitabine alone if ctDNA (–). For patients after adjuvant chemotherapy if ctDNA (+) they received folinic acid–5FU–irinotecan (FOLFIRI), de-escalated to capecitabine if ctDNA (–) after capecitabine, or escalated to capecitabine + oxaliplatin if ctDNA (+).

Among 135 patients included in the per-protocol population, 35 (26%) patients had ctDNA (+) after surgery. After 3-month of capecitabine + oxaliplatin, 11/35 (31%) patients converted to ctDNA (–), but 8/11 (73%) eventually relapsed or became ctDNA (+) again. Of 24 patients who received FOLFIRI after capecitabine + oxaliplatin, 13 (54%) remained ctDNA (+) (6 of whom relapsed), and the remaining 11 (46%) converted to ctDNA (–) and continued to be relapse free at the time of analysis (median follow-up 21.2 months).

The study illustrates the benefit of ctDNA-guided treatment and suggests that treatment with FOLFIRI may be useful in post-adjuvant ctDNA (+) patients. (Abstract LBA28)

GALAXY/CIRCULATE-Japan

In a prospective analysis of 2280 patients with resected stage I-IV CRC, patients with ctDNA (+) at postoperative week 4 had a significantly inferior DFS compared to ctDNA (–) individuals (24-mo DFS: 89% vs. 31%; HR 16.9, p<.0001).

Adjuvant chemotherapy appears to provide no benefit in ctDNA (–) patients (24-mo DFS 88% vs. 90% in the chemotherapy and no chemotherapy groups; HR 1.39, p=0.2). The benefit of adjuvant chemotherapy was evident in ctDNA (+) patients (24-month DFS: 39% vs 16%; HR 3.29, p <0001), particularly with 6 months of treatment.

ctDNA dynamics between 4-12 weeks influenced DFS: the best in continuously ctDNA (–) patients, then in ctDNA clearance (positive to negative), then in ctDNA reemergence (negative to positive), and the worst in continuously ctDNA (+) patients. (Abstract 558MO)

NICHE-3

In patients with resectable dMMR/MSI-H colon cancer (stage II-III), the administration of two preoperative (that is, before surgery) doses of nivolumab + relatlimab (anti-LAG3) led to pCR rate of 79% (15/19). Pathological responses were observed in all treated patients.

NICHE-3 trial confirmed what has been seen in previous NICHE trials: immunotherapy works well in early MSI-H colon cancer. (Abstract LBA31)

KRAS G12C Inhibitor-Centered Trials

Two clinical trials with KRAS G12C inhibitors combined with anti-EGFR antibodies confirm activity in KRAS G12C mutant metastatic CRC.

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In a phase III randomized study, sotorasib + panitumumab (sotorasib: 960 mg or 240 mg daily) was compared to trifluridine/tipiracil or regorafenib (standard of care, control arm) in KRAS G12C-mutated mCRC. Both arms with soto + pani improved the primary endpoint of PFS compared to the control arm. The combination of sotorasib and panitumumab resulted in significantly improved PFS (5.6 months, for soto-pani 960 mg, vs 2.2 months for control arm), and ORR was also improved in the experimental arm, with 26% for the higher dose. Overall survival (OS) was not different, but the analysis is still immature. (Abstract LBA10)

KRYSTAL-1 Update

The median PFS of adagrasib plus cetuximab was 6.9 months and ORR was 46%. (Abstract 549O)

It is interesting that though both sotorasib and adagrasib are G12C inhibitors, the combination of adagrasib + cetuximab had better responses in terms of objective response rates (46% versus 26% for sotorasib + panitumumab) as well as PFS (6.9 months for adagrasib + cetuximab versus 5.6 months for sotorasib + panitumumab). It is a bit disappointing that even with combined inhibition of KRAS G12C and EGFR, the response rates and median PFS are not as significant as patients would like. Nevertheless, having more drug combinations is much needed and anything that adds more time for more patients is much welcomed.

CAIRO 5

Triplet CTx + bev in right-sided/RAS/RAF mutant, and doublet + anti-EGFR in left-sided RAS/RAF-wt mCRC fail to improve OS.

In the randomized phase III trial CAIRO5, patients with initially unresectable CRC liver metastases were treated with bevacizumab + FOLFOXIRI or FOLFOX/FOLFIRI (if right-sided and/or RAS/BRAF V600E-mutated – group 1), or with FOLFOX/FOLFIRI + panitumumab or bevacizumab (if left-sided and RAS/BRAF V600E wild-type – group 2).

In group 1, despite previously reported benefit in ORR and PFS with triplet CHT + bev over double CHT + bev, no improvement in OS was seen (mOS: 23.6 vs 24.1 mo; HR 0.92, 95% CI 0.70-1.20, p=.52).

In group 2, in agreement with the previously reported lack of improvement in PFS (HR 1.11, 95% CI 0.48-1.48, p = .46), OS was not different in FOLFOX/FOLFIRI + bevacizumab and FOLFOX/FOLFIRI + panitumumab arms (mOS: 40.4 vs 38.2 mo, respectively; HR 1.02, 95% CI 0.72-1.46, p=0.89). ORR was higher with panitumumab than with bevacizumab (80% vs 53%), but R0/1 resection rate was similar (58% vs 58%).

No significant differences in overall survival rates were observed between the different regimens. Therefore, patients can opt for systemic treatment with the least toxicity. (Abstract LBA27)

IDEA/ACCENT

The role of KRAS/BRAF mutations for early-stage colon cancer was investigated in IDEA/ACCENT pooled analysis.

In a pooled analysis of 7 trials evaluating the duration of adjuvant chemotherapy in resected stage III CRC, the prognostic impact of MMR status, and KRAS and BRAF V600E mutations were tested. Five-year recurrence rate was 29% in MSS/pMMR, and 21% in MSI/dMMR cancers.

In MSS/pMMR tumors, KRAS (both codon 12 & 13) and BRAF mutations negatively impacted DFS vs wild-type cancers (HR 1.41 & 1.58, respectively), OS (HR 1.35 & 2.06), and survival after recurrence (HR 1.25 & 2.87).

In MSI/dMMR tumors, no impact of KRAS or BRAF mutations on DFS was seen (HR 0.99 & 0.98), however BRAF mutations had a negative effect on OS (HR 1.36), and KRAS and BRAF mutations worsened survival after recurrence (HR 1.52 & 1.99). (Abstract 553O)

ASCOLT

Patients with Dukes’ C (stage III) and high-risk Dukes’ B (high-risk stage II) colorectal cancer were randomized to aspirin 200 mg daily or placebo for 3 years after surgery and completion of standard adjuvant therapy.

The primary endpoint of DFS was not improved with aspirin (HR 0.91; 95% CI 0.73-1.13, p=.38). OS was also similar (HR 0.75, 95% CI 0.53-1.07, p = .11). The adjuvant role of aspirin appears to be limited. (Abstract LBA29)

2022

We interviewed Annie, one of Fight CRC RATS volunteers, to help unpack the most important findings for our community recently presented at ESMO.

ESMO 2022 Research News

Immunotherapy for MSI Colon Cancer

Q: Earlier this year, at ASCO, we heard about remarkable results from immunotherapy (anti-PD1) for some rectal cancer patients – those with stage II and III, deficient mismatch repair system/microsatellite instability (dMMR/MSI-H) rectal cancer. And the good news continued at ESMO, for the MSI colon cancer subset of patients, now with a combination of immunotherapies. Can you tell us more about it?

The NICHE-2 study received a standing ovation at ESMO 2022. Dr. Myriam Chalabi, from the Netherlands, presented data for response to one dose of immunotherapy for stage III colon cancer patients with MSI. The trial showed 95% major pathologic responses (67% were Pathological Complete Responses, “pCR”).

A lesser known result: The study also showed an increased response for Lynch Syndrome patients (78% pCR vs. 58% pCR).

Fifteen percent of all colorectal cancers are part of the MSI subtype (about 10% of stage III colon cancer patients). Right now, for immunotherapy options, there is the ATOMIC trial (immunotherapy after chemo) and the StandUp2Cancer trial (immunotherapy after chemo if there is a positive circulating tumor DNA (ctDNA) result). Chemotherapy with oxaliplatin can bring on neuropathy side effects (which can affect one’s ability to work in many careers or can increase risk of falling for elderly patients). For stage III colon cancer patients, surgery side effects, while manageable, are not minimal (bowel issues). Having a trial where surgery or chemo may be avoided would be an exciting option for patients and worthy of discussion with an expert oncologist.

FRESCO-2 Trial: Fruquintinib

Q: What about some news for all patients (with colon or rectal cancer), regardless of mutations or microsatellite status? We’re always looking to hear about phase III trials that may result in the approval of new therapies, leading to a change of practice.

Options for stage IV patients in later lines after progression on chemo are limited. So the phase III FRESCO-2 trial looking at Fruquintinib (approved in China in 2018) was to demonstrate safety and efficacy. FDA approval is possible in the coming months (it was Fast Tracked in June 2020). The trial demonstrated benefit to patients, as well as tolerable side effects of the treatment.

There have been 33 trials in China, four in the U.S. (one of which was also recruiting in Europe), and one in Australia for fruquintinib. There are two trials open in the U.S. (one of which is for colorectal cancer patients and is combining immunotherapy: NCT04577963). There are 23 trials open in China as researchers are combining fruquintinib with other chemotherapies, biologics, or immunotherapies, as well as moving the use of fruquintinib into earlier lines of therapy.

Patients will want to consider possible benefits, as well as side effects especially as compared to options such as regorafenib (Stivarga®) or TAS-102 (also known as trifluridine–tipiracil) (Lonsurf®). Although there are patients who benefit from Stivarga and Lonsurf, the side effects can be problematic.

KRAS G12C Targeted Therapies

Q: Have there been any findings pertinent for those with colorectal cancer with particular mutations? Any news from the targeted therapies front?

In colorectal cancer, a monotherapy (a targeted drug given on its own) did not give enough benefit for an approval. Researchers working in another colorectal cancer mutation, BRAF V600E, learned in the BEACON study that using a dual blockade of a targeted treatment with an EGFR inhibitor worked for better response for BRAF V600E patients (which led to the BEACON doublet becoming FDA-approved standard of treatment).

Similarly, for KRAS G12C colorectal cancer treatment, researchers have added in an EGFR inhibitor: cetuximab (with adagrasib, in the KRYSTAL-1 trial) or panitumumab (with sotorasib, in the CodeBreak-101 study). Both clinical trials are now showing improvement in response rate, progression free survival, and overall survival for patients in the KRYSTAL-1 and the CODEBREAK-101 trials.

Although KRAS G12C makes up about 2% of colorectal cancers, this dual MAPK pathway inhibition may become a strategy in other targeted KRAS trials. These trials are now in early monotherapy phase trials seeking to establish safety and efficacy. Other MAPK pathway interventions being considered: SHP2 inhibitor, SOS-1 inhibitor, MEK inhibitor, and ERK inhibitors.

Because of the discovery that KRAS G12C was “druggable,” there has been a lot of research and investment in a variety of KRAS targeted approaches. The trials are offered in the second-line metastatic setting, but there are also KRAS trials for those with minimal residual disease (NED on scans, positive ctDNA result).

This area of KRAS research is moving fast, and for the 40% of stage IV patients with a KRAS mutation, checking in on KRAS research at all the important conferences is well-recommended.

MOUNTAINEER-2: HER2+ Colorectal Cancer

MOUNTAINEER-2 trial results continued its trifecta of summer oncology conference presentations (ASCO, World GI, ESMO). This non-chemotherapy trial is for HER2 positive (HER2+) colorectal cancer patients. Response rates are quite good, and treatment side effects manageable.

Although HER2+ is not common (about 3%) of all colorectal cancer patients, about one out of seven rectal cancer patients have this targetable mutation. It’s also more common with left-sided colon cancer patients, so testing for this mutation is well-advised!

Dr. Strickler noticed that HER2+ patients responded differently to a treatment and approached a pharma company Seattle Genetics with an investigator-initiated study. Because of early positive results of the first MOUNTAINEER trial, the NCCN Guidelines now include the suggestion that oncologists consider trials with trastuzumab (Herceptin®) in combination with other medications as a second-line option. At this annual ESMO Congress, Dr. Strickler reported the results from the phase II MOUNTAINEER-2 study.

The next trial, the MOUNTAINEER-3 study, is now at 25 locations, enrolling 400 patients, and is moving this treatment into a first-line setting. The trial will test if response rates may be even higher in an earlier line of treatment and if there is a longer durable response to this well-tolerated treatment. The trial is also open to stage III HER2+ patients who progress to stage IV (if chemo was completed more than six months prior to enrollment).

This was a great overview of news from ESMO 2022 that affects, impacts, and matters to us. Thank you, Annie, for helping us to understand the progress and where the research is headed!

In this month’s clinical trial conversations blog, Maia and Manju review the Evaluating Radiation, Ablation, and Surgery (ERASur; NCT05673148, A022101/NRG-GI009) trial, a phase III study for patients with limited metastatic colorectal cancer (mCRC) alongside Dr. Eric Miller, principal investigator (PI) of the trial and a GI radiation oncologist at the Ohio State University Comprehensive Cancer Center. Special thanks to Dr. Miller for contributing to this blog.

Highlights of the ERASur trial:

• Who: Stage IV patients, MSS, BRAF wildtype, no liver-only metastases or mets to the peritoneum or omentum.
• What: Comparing outcomes of patients with ablative therapies + systemic therapy to systemic therapy only
• When: Active since 2023
• Where: 100 locations nationwide, additional locations added monthly
• Why: To improve overall survival for patients with limited metastatic disease

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

• GI ASCO Updates
• Noninvasive Trials for CRC Screening

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.

What is the primary objective of the ERASur study?

Dr. Miller: The primary objective of ERASur is to answer this question – Do patients with limited metastatic colorectal cancer live longer if we treat all sites of disease with ablative therapy (e.g., surgery, radiation, and thermal ablation) and standard-of-care chemotherapy (a systemic therapy) or standard-of-care chemotherapy alone?

For patients with stage IV colorectal cancer that has only spread to the liver, we know that there is a benefit when the metastatic tumors are treated with both ablative therapy and systemic therapy. However, for patients with metastatic disease that has spread to sites other than the liver or who have metastases of the liver and other sites in the body, we don’t know if there is a benefit to adding ablative treatment to all sites of metastatic disease along with systemic therapy or if treatment with systemic therapy alone is enough to improve survival.

Without a benefit to adding ablative treatment to systemic therapy, patients could spend needless extra time and money traveling to appointments or experience unwanted and unnecessary side effects of ablation therapy.

Without a benefit to adding ablative treatment to systemic therapy, patients could spend needless extra time and money traveling to appointments or experience unwanted and unnecessary side effects of ablation therapy.

When can patients enter and what are the study inclusion criteria for patients with metastatic CRC (colorectal cancer)?

Dr. Miller:  Patients can enter the study early by pre-registering before they start standard-of- care therapy (systemic therapy) or anytime up to completing 39 weeks of systemic therapy.

The inclusion criteria for pre-registration are straightforward: a diagnosis of metastatic colorectal cancer either through a biopsy of the primary tumor or a metastatic site, the tumor must be microsatellite stable and BRAF V600E wild-type (no BRAF V600E mutation present), and no liver-only metastatic disease or peritoneal/omental metastasis.

Patients can register for the study as long as they have not developed new or enlarging metastases during initial systemic therapy, completed a minimum of 12 weeks and a maximum of 39 weeks of systemic therapy, and have 4 or fewer sites of disease remaining after initial systemic therapy on repeat imaging. A single “site” of disease is defined as each liver lobe (right and left), each lobe of the lungs, each adrenal gland, lymph nodes addressable in a single surgery or radiation field, and bone metastases that can be treated in a single radiation field. Importantly, there are no restrictions on the number of tumors per site. For example, if a patient has 3 tumors in the right lobe of the liver or 3 tumors in the right upper lobe of the lung, those are each considered one site of disease. The primary tumor also needs to be either already removed surgically or amenable to surgical removal.

As of August 2024, the trial is open in the following states: Arizona, California, Florida, Georgia, Iowa, Idaho, Kentucky, Maryland, Michigan, Minnesota, Missouri, Mississippi, Montana, North Dakota, Nebraska, New Jersey, New Mexico, Nevada, New York, Ohio, Oklahoma, Pennsylvania, South Dakota, Tennessee, Texas, Utah, Wisconsin.

What treatments are being compared in the ERASur study?

Dr. Miller: Following completion of initial systemic therapy (12-39 weeks), patients who meet eligibility criteria are randomized to either total ablative therapy (TAT) plus systemic therapy or systemic therapy alone. For patients in the TAT group, the treatment team will decide on which ablative therapies are appropriate to address all areas of disease. Those therapies may include surgical removal, stereotactic body radiation therapy (high doses of radiation delivered in a precise manner to ablate the tumor), and/or microwave ablation (focused heat to kill the tumor). Following TAT, it is left to the treatment team and patient to come to a joint decision about continued systemic therapy. In both the TAT group and the systemic therapy alone group, there is a lot of flexibility regarding treatment. Patients can continue systemic therapy, transition to maintenance systemic therapy, or go on a treatment break at any time.

What are the expected outcomes or endpoints being measured in the ERASur study?

Dr. Miller: The primary endpoint in the study is overall survival – comparing patients in the TAT group to those in the systemic therapy alone arm. We have additional secondary endpoints of event-free survival, toxicity of the treatments, and local control of metastatic disease in patients treated with TAT. Of note, we also have an optional blood collection in the study with planned future ctDNA analysis.

How does the trial address patient participation barriers?

Dr. Miller: Leaving as many decisions as possible to the treatment team and patient is one of the ways that we have made this trial pragmatic. We also permit patients to receive systemic therapy closer to their home and not necessarily at the site where they register for the trial which helps make participation in the trial much more feasible for patients who don’t live close to a site where the trial is open. I want to acknowledge the outstanding input from Manju and her colleagues from COLONTOWN for their input in making this truly a pragmatic trial.

To continue learning about the ERASur trial, check this X (Twitter) thread by @CrcTrialsChat, with short videos with the three Principal Investigators, and also this DocTalk of Manju with them, posted on Colontown University.  You can also view this clinical trial in Fight CRC’s Clinical Trial Finder.

Acknowledgements: The PIs of the ERASur trial: Dr. Eric Miller, GI radiation oncologist and member of the Translational Therapeutics Program at the Ohio State University Comprehensive Cancer Center –James; Dr. Paul Romesser, radiation oncologist and early drug development specialist, director of Colorectal and Anal Cancer, Department of Radiation Oncology, at the Memorial Sloan Kettering Cancer Center, New York; and Dr. Kate Hitchcock, Clinical Associate Professor, Department of Radiation Oncology, University of Florida Health Cancer Center.

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  for more information on trials.