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.

Participantes: 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).

Resultados: 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).

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

Diseño del estudio: 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.

Resultados: 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.

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.

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

Diseño del estudio: This was a two-armed study:

1. 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.
2. 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.

Resultados: 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.

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.

Participantes: 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.

Diseño del estudio: 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.

Resultados: 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.

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.

Participantes: 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.

Diseño del estudio: 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.

Resultados: 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.

• 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.

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: NEST-1 clinical trial (NCT05571293)

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

The NEST-1 trial 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): First results of the CheckMate 8HW study (NCT04008030)

Abstract LBA768; Thierry Andre, MD

The CheckMate 8HW trial 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? Data from 2 international registries in rectal cancer

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.

Researchers arrived at this conclusion with a retrospective analysis of data from two international registries in rectal cancer (two prospectively maintained registries). However, the study period might not have accounted for the recent advancements or changes in treatment protocols, potentially influencing the observed outcomes.

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.”

There is so much to learn about this approach. For those interested, watch this recent presentation by Dr. Rodrigo Perez, from Sao Paulo, Brazil, discussing the risk of local regrowth after watch and wait in rectal cancer, hosted by Manju.

Tumor genetics and sidedness predict outcomes
Tumor genomics and sidedness to predict outcomes in metastatic colorectal cancer (mCRC) (multivariable analysis on US-based de-identified database originating from approximately 280 US cancer clinics (1/2011–3/2023))

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: The randomized AGITG DYNAMIC-Rectal study (ACTRN12617001560381)

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). This treatment involves giving chemoradiation (chemoRT) before surgery for locally advanced rectal cancer. 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 cumulative probability of distant recurrence at three years was three times higher for ctDNA(+) patients who had adjuvant chemo, while the locoregional recurrence was 11 times higher when compared to ctDNA(-) patients who did not get chemo.

The authors concluded that a ctDNA-guided approach after neoadjuvant chemoRT and surgery was associated with lower chemo use. The main sites of recurrence in the 15 ctDNA(-) patients who recurred were lung only (80%), peritoneum and lung (7%), and lymph node only (13%).

BESPOKE CRC study
Circulating tumor DNA (ctDNA) for informing adjuvant chemotherapy (ACT) in stage II/III colorectal cancer (CRC): Interim analysis of BESPOKE CRC study (NCT04264702)

Abstract 9; Pashtoon Murtaza Kasi, MD

These are the first results of the BESPOKE CRC observational trial (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. Of the ctDNA(+) patients, 39.1% became ctDNA(-) at 12 weeks after surgery, and these patients had almost half the recurrence rates of patients who continued to be ctDNA(+), but they did worse than those who were ctDNA(-) at the four weeks and 12 weeks post-surgery.

About half of the patients who cleared ctDNA on adjuvant chemotherapy turned positive later, and they showed cancer on scans. CtDNA results during surveillance were available for 339 patients; 8.3% (58/339) were ctDNA(+) and had significantly worse DFS compared to patients that were ctDNA(-) throughout the surveillance period.

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: Updated analysis from GALAXY study in the CIRCULATE-JAPAN (UMIN000039205)

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. This group underwent chest, abdomen, and pelvis CT scans every six months. 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), defined as the time between surgery and detection of relapse/death due to any cause.

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. Also, among MRD(+) patients treated with adjuvant chemotherapy, a 50% or greater decrease in ctDNA levels at six months was associated with better DFS than those with less than a 50% decrease or an increase in ctDNA levels.

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: NRG-GI005 (COBRA) phase II/III study (NCT04068103)

Abstract 5; Van Morris, MD

The COBRA trial 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. The primary endpoint for the phase II study was clearance of ctDNA at six months. A pre-planned “futility analysis” looked at the first 16 ctDNA(+) patients at baseline between the two arms to check if the ctDNA clearance was as the trial predicted in the chemotherapy arm so the study could proceed as planned.

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.

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. (“Response” is a tumor reduction of greater than 30%, with stable disease at +/- 30%). 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.

The SLI in this trial was designed to assess the toxicity of encorafenib/cetuximab plus chemotherapy (FOLFOX or FOLFIRI) before conducting the phase 3 study. For this SLI, some patients who already had first-line treatment were admitted.

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.

Trifluridine/tipiracil plus bevacizumab for third-line treatment of refractory metastatic colorectal cancer: The phase 3 randomized SUNLIGHT study.

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.

Durvalumab and tremelimumab plus local tumor ablation (RFA or stereotactic radiotherapy) in patients with metastatic colorectal cancer with unresectable liver metastases: Results of the EORTC-1560-GITCG (ILOC) phase II study.

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.

Phase Ib open-label study to evaluate safety, tolerability, immunogenicity, and efficacy of multiple subcutaneous injections of PolyPEPI1018 vaccine as an add-on immunotherapy to TAS-102 in participants with late-stage microsatellite-stable metastatic colorectal cancer (MSS mCRC; OBERTO-201).
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 patients in the two groups were similar and the common clinical stage was stage III. 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. Overall survival and disease-free survival and rate of distant metastases were similar between the two groups. The local regrowth rates for patients who entered watch and wait were 36% (LCRT) and 20% for SCRT.

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. The retrospective nature of this study and short follow-up are major limitations, and this study does not report data on treatment toxicity.

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. It seems there is a lot of variability in the use of 5FU bolus in the treatment of stage IV CRC, but there haven’t been studies looking at the impact of bolus 5-FU on overall survival (OS).

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.

Negative hyperselection of patients with RAS wild-type metastatic colorectal cancer for panitumumab: A biomarker study of the phase 3 PARADIGM trial.

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). The PARADIGM biomarker study (n=733 )looked at potential biomarkers related to primary and secondary resistance to each therapy using tumor tissue and circulating tumor DNA (ctDNA). ctDNA was tested using a custom panel that looked at a large number of DNA changes including mutations, amplifications, and rearrangements. Hyperselection status — whether the checked genes were mutated or not — was correlated with OS, progression-free survival (PFS), and response rate (RR) in the PARADIGM population.

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) and the results of a new escalation (ESC) cohort of 40 mg to 80 mg regorafenib, where the starting dose of regorafenib was 40mg in the first cycle and increased to 80 for the next cycles.

Patients with chemorefractory MSS mCRC got RIN at regorafenib: 80 mg daily for a 28-day cycle, ipilimumab at 1 mg/kg every six weeks and nivolumab at 240 mg every two weeks. This dosing was given to six evaluable patients and if no more than one dose limiting toxicity (DLT) was noted, this was the dose used in the expansion cohort. Following RP2D establishment, the protocol was changed to explore a 10-patient cohort with 40 mg/day regorafenib for cycle 1 with escalation to 80 mg/day for cycle 2 and beyond.

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. Early circulating tumor DNA (ctDNA) clearance and treatment response was looked at in this study.

RIN (80/1/240) has substantial activity in MSS mCRC patients with no liver mets. Even though regorafenib dose reduction in cycle 1 reduced skin and other immune-mediated toxicities, the results were not as good. 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.

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.