Are you curious about the latest scientific findings presented at the ASCO Gastrointestinal Cancers Symposium (GI ASCO 2024) on January 18-20? In this month's Clinical Trial Conversation, patient advocates Maia and Manju comment on the most compelling research from the conference.

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.

Since science can be difficult to unravel and understand, Fight CRC has hosted a conversation with Dr. Morris, in which he discussed, in an easy-to-understand way, the research findings highlighted here by Maia and Manju:

Join GI medical oncologist Van Morris, MD, Fight CRC Research Advocacy Project Manager Carli King, PhD, and Fight CRC RATS Member Lee Jones as they unpack exciting new colorectal cancer research presented at GI ASCO 2024.

Be Sure to Check Out These Fight CRC Resources:

Clinical Trial Finder

• Colorectal Cancer Clinical Trial Finder
• Colorectal Cancer Clinical Trials Brochure

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