This month’s Clinical Trial Conversations features detailed summaries of 4 study abstracts presented during the European Society for Medical Oncology (ESMO) Congress 2024. The ESMO Congress is an annual meeting that hosts clinicians, researchers, patient advocates, and other stakeholders from across the globe to present the latest cutting-edge data in oncology. The highlighted study abstracts, curated by Maia and Manju, were selected due to their significance for the colorectal cancer community.   

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.

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