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.

Here are the studies that Maia and Manju are most excited about from 2022 GI ASCO
Maia:
First up from 2022 GI ASCO is the phase Ib/II trial of onvansertib (PCM-075, PLK1 inhibitor) in combination with FOLFIRI + bevacizumab in second-line treatment of KRAS-mutated metastatic colorectal cancer (mCRC). In second-line treatment of mCRC patients with diverse KRAS mutations, the combination of onvansertib and FOLFIRI-bev was well-tolerated. There were low-grade treatment-emergent adverse events, which were tolerable, and it showed a promising overall response rate (ORR) of over 30% and progression-free survival over nine months. The study showed that an early decline in the presence of mutant KRAS in plasma (that is, just after the first cycles of treatment) was correlated with response. This means that it may be a viable biomarker for exploration in the future. (Abstract #100 Trial NCT03829410)

In the trial, ongoing at the University of Colorado, five patients achieved a partial response, 24 patients reached stable disease, and 29 patients derived a clinical benefit at the first re-staging at two months. In the poster presented during the meeting, the authors concluded: “Toxicity from these three approved drugs is well-established and observed toxicity in this trial was as expected,” […] “The combination…has promising activity in treatment-refractory mCRC with some patients achieving deep and durable responses and a majority of patients deriving clinical benefit at time of first disease re-staging.” (Abstract #118 Trial NCT03475004)

There were a couple of clinical trials that combined immunotherapy with the approved, standard therapies for mCRC that did not have good results. Although the results were disappointing, they show us what does not work, or works partially, which is a step in the right direction: With more accurate information, patients and doctors are able to make better decisions about what treatments are worth pursuing. As advocates, we’re grateful for all results being shared!

One of those trials was the phase I/II study of regorafenib (rego) and pembrolizumab (pembro) in refractory microsatellite-stable (MSS) CRC. It did not meet its primary end-point for phase II: significant improvement in progression-free survival (PFS). Median PFS was 2.0 months, which did not meet the prespecified PFS of 2.85 months. Median overall survival (OS) was 9.6 months. The most common adverse events were just the usual/typical ones from the drugs, and the doses of those drugs, used in the trial. Given its negative result, the researchers analyzed data beyond what was planned in the trial design (post hoc analysis): The analysis revealed that patients with no liver metastases and those treated with prior radiotherapy achieved longer PFS. More studies will be searching for biomarkers/specific characteristics to determine subgroup(s) of patients who may benefit from these treatments. (Abstract #15 Trial NCT03657641)

The other trial that did not meet expectations was nivolumab plus mFOLFOX6 and bevacizumab for first-line treatment of mCRC. Researchers shared the results from the phase II of this phase II/III clinical trial, CheckMate 9X8, that investigates investigates the addition of the immunotherapy nivolumab (Opdivo) to first-line standard-of-care (mFOLFOX6 and bevacizumab) of mCRC. The combination did not demonstrate a statistically significant improvement in PFS, compared to SOC alone. Even if the primary endpoint of PFS was not met, nivolumab + SOC showed higher PFS rates after 12 months, a higher response rate, and more durable responses compared with SOC, along with acceptable safety, in first-line treatment. This indicates that further research is required to identify patients’ characteristics of a subgroup of mCRC that might benefit with the combination in the first-line treatment. (Abstract #8 Trial NCT03414983)

Manju:
An amazing and potentially practice-changing study of Induction PD-1 Blockade in Subjects With Locally Advanced Mismatch Repair Deficient Solid Tumors had a complete clinical response rate of 100% for rectal cancer. (Trial NCT04165772)

This was one of the most exciting results from 2022 GI ASCO. Early stage or locally advanced (stage II or stage III) MSI-H rectal cancer accounts for about 5%-10% of all rectal cancers. A large proportion of MSI-H rectal cancer is made up of Lynch syndrome patients, who may be quite young. Currently, all patients with locally advanced rectal cancer get treated with a combination of chemo-RT, chemotherapy, and surgery. For patients with MSS rectal cancer, this aggressive treatment is quite effective in curing their cancer, but many patients are left with long-term life-altering side effects from radiation, chemotherapy and surgery. Patients with MSI-H rectal cancer may not respond as well to 5FU containing chemotherapy. Studies have shown that immunotherapy works well in advanced (metastatic) MSI-H colorectal cancer.

An amazing and potentially practice-changing study of Induction PD-1 Blockade in Subjects With Locally Advanced Mismatch Repair Deficient Solid Tumors ha respond as well to 5FU containing chemotherapy. Studies have shown that immunotherapy works well in advanced (metastatic) MSI-H colorectal cancer.

The idea of the small phase II study conducted at Memorial Sloan Kettering Cancer Center was to see how effective immunotherapy is in early stage disease and to use it in place of chemotherapy for patients with locally advanced MSI-H rectal cancer. Patients with a complete response to immunotherapy alone would have the option of omitting radiation and surgery and thus be spared side effects from both. In the study, patients with locally advanced deficient mismatch repair (dMMR) or MSI-H rectal cancer (stage II and stage III rectal cancer) were treated with a single agent PD-1 inhibitor, dostarlimab, for six months. Response was assessed at the end of treatment with PD-1 inhibitor. If the patients had a clinical complete response, they could undergo observation and forgo radiation and surgery. If they did not have a complete response, they would receive standard chemo-RT and then be evaluated again to potentially avoid surgery.

The response rate to the PD-1 inhibitor was presented. So far, 16 patients were enrolled, of which 11 completed the six months of PD-1 inhibitor. All 11 patients showed a complete clinical response and, therefore, did not need chemo-RT or surgery and are being followed up with observation. These results suggest a new approach for treatment of MSI-H locally advanced rectal cancer, where treatment with PD-1 inhibitor alone may potentially help avoid chemo-RT and surgery, and the associated long-term side effects. Further patient accrual is ongoing, and this trial is certainly on my list to watch closely. (Abstract #16)

There were also promising and much awaited results for the phase I/II trial of Encorafenib, Cetuximab, and Nivolumab in Treating Patients With Microsatellite Stable, BRAFV600E Mutated Unresectable or Metastatic Colorectal Cancer. (Trial NCT04017650)

Though the Beacon doublet (encorafenib+cetuximab, E+C) is a much welcome new treatment for MSS BRAF V600E mutated metastatic CRC, the response time is not as long as patients would like it to be. This E+C+N trial tests if targeting BRAF, EGFR, and PD-1 simultaneously, could result in more efficacy/ better treatment. In this single arm study done at MD Anderson Cancer Center as a phase I/II trial, MSS mCRC patients with tumors having a BRAFV600E mutation who have progressed on one or two previous lines of therapy, but have not yet had BRAF, EGFR or MEK inhibitor or immunotherapy, were enrolled. The trial looked at the best overall response and safety/tolerability of the combination.

There were also promising and much awaited results for the phase I/II trial of Encorafenib, Cetuximab, and Nivolumab in Treating Patients With Microsatellite Stable, BRre efficacy/ better treatment. In this single arm study done at MD Anderson Cancer Center as a phase I/II trial, MSS mCRC patients with tumors having a BRAFV600E mutation who have progressed on one or two previous lines of therapy, but have not yet had BRAF, EGFR or MEK inhibitor or immunotherapy, were enrolled. The trial looked at the best overall response and safety/tolerability of the combination.

So far, 26 patients have been enrolled, of which 22 were evaluable for response. No dose-limiting toxicities were seen, but grade 3-4 treatment-related adverse events occurred in four out of 22 patients, and a headache was the most commonly reported treatment-related side effect in all patients who had any side effects. An overall response rate of 50% (11 out of 22), disease control rate of 96%, median PFS of 7.4 months, median OS of 15.1 months, and median duration of response of 7.7 months makes this a very promising treatment combination for this subset of patients with poor survival. Of the 11 patients who continue to remain on the study, two patients are now at 100 weeks of treatment. The follow-up randomized Phase II SWOG 2107 trial is coming soon where 75 patients will be randomized 2:1 to E+C+N vs. E+C. (Abstract #12)