2023 GI ASCO Clinical Trial Studies


Clinical Trial Conversations
hero symbol

The 2023 ASCO® Gastrointestinal Cancers Symposium (2023 GI ASCO) took place in San Francisco January 19–21, celebrating its 20th anniversary. Researchers from around the world gather each year to present the latest research and advances in GI cancers. Maia and Manju, our clinical trial champions, outline relevant studies and advances of interest for the colorectal cancer community.


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.


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.

Stay Tuned for More!

Once a month, Maia and Manju 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.

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. 

In this series, we hope to cover promising trials that are enrolling, lessons learned from past research, logistics and resources to joining a clinical trial, and provide relevant and timely updates for our colon and rectal cancer community. 

Be Sure to Check Out These Fight CRC Resources:

Clinical Trial Finder

More Clinical Trial Conversations