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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Patients with RAS wildtype metastatic CRC (mCRC) are often treated with chemotherapy in combination with an EGFR inhibitor in the first line setting. There is preliminary evidence suggesting that patients who progress may benefit from rechallenge (reintroduction) with EGFR inhibitors in later lines of treatment. The clinical trial highlighted below aims to determine whether rechallenge with an EGFR inhibitor can improve outcomes in select patients in the third line treatment setting.

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

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

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

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

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

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

PEGASUS

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

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

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

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

GALAXY/CIRCULATE-Japan

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

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

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

NICHE-3

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

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

KRAS G12C inhibitor-centered trials

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

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

KRYSTAL-1 update

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

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

CAIRO 5

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

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

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

In group 2, in agreement with the previously reported lack of improvement in PFS (HR 1 .11, 95% Cl 0.48-1.48, p = .46), OS was not different in FOLFOX/FOLFIRI + bevacizumab and FOLFOX/FOLFIRI + panitumumab arms (mOS: 40.4 vs 38.2 mo, respectively; HR 1 .02, 95% Cl 0.72-1.46, p=0.89). ORR was higher with panitumumab than with bevacizumab (80% vs 53%), but R0/1 resection rate was similar (58% vs 58%). It has been hypothesized that comparable OS in both arms may be partially attributed to a high resection rate in the study.

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

IDEA/ACCENT

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

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

In MSS/pMMR tumors, KRAS (both codon 12 & 13) and BRAF mutations negatively impacted DFS vs wild-type cancers (HR 1 .41 & 1.58, respectively), OS (HR 1.35 & 2.06), and survival after recurrence (HR 1.25 & 2.87).

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

ASCOL T

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

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

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

ESMO 2022 Research News

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

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

A lesser known result: The study also showed an increased response for Lynch Syndrome patients (78% pCR vs. 58% pCR). Dr. Chalabi talks about the NICHE-2 study in this ESMO22 interview.

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

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

Options for stage IV patients in later lines after progression on chemo are limited. So the phase III FRESCO-2 trial looking at Fruquintinib (approved in China in 2018) was to demonstrate safety and efficacy. FDA approval is possible in the coming months (it was Fast Tracked in June 2020). The trial demonstrated benefit to patients, as well as tolerable side effects of the treatment. This interview with Dr. Arvind Dasari explains the trial results (along with some of his ESMO22 slides).

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

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

Post chemotherapy, oncologists have to look at many factors in prescribing a treatment for their patients (risk factors, comorbidities, etc.), since hypertension was one of the grade 3 side effects, that may be relevant to their recommendation for fruquintinib. The trial was a comparison against a placebo, so oncologists will be looking at historical data for Lonsurf® and Stivarga® for progression free survival. But the reported ESMO side effects data may be very important for their recommendations.

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

But in colorectal cancer, a monotherapy (a targeted drug given on its own) did not give enough benefit for such an approval. Researchers working in another colorectal cancer mutation, BRAF V600e, learned in the BEACON study that using a dual blockade of a targeted treatment with an EGFR inhibitor worked for better response for BRAF V600e patients (which led to the BEACON doublet becoming FDA-approved standard of treatment).

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

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

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

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

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

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

In the past few years, KRAS G12C targeted treatments have been enrolling patients across tumor types. One-treatment sotorasib (Lumakras®) has an FDA-accelerated approval for non-small cell lung cancer.

Dr. Strickler is rather a quiet hero of scientific research. He noticed that HER2+ patients responded differently to a treatment and approached a pharma company Seattle Genetics (not to be confused with SEAGEN, which is a different company) with an investigator-initiated study. Because of early positive results of the first MOUNTAINEER trial, the NCCN Guidelines now include the suggestion that oncologists consider trials with trastuzumab (Herceptin®) in combination with other medications as a second-line option. At this annual ESMO Congress, Dr. Strickler reported the results from the phase II MOUNTAINEER-2 study.

Interview with Dr. Strickler (from ESMO World GI, July 2022) on how tucatinib plus trastuzumab yields clinically meaningful antitumor activity in HER2+ metastatic colorectal cancer.

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

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