2023 ASCO: The research progress of 4 new targets of colorectal cancer
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2023 ASCO: The research progress of 4 new targets of colorectal cancer
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2023 ASCO: The research progress of 4 new targets of colorectal cancer is summarized
Colorectal cancer (CRC) is the third most common malignancy in the world. Chemotherapy is the cornerstone of CRC treatment, but its clinical application is limited due to inevitable drug resistance, narrow mechanism of action and adverse reactions. Moreover, there are very few options after chemotherapy resistance, and an efficient and tolerable regimen is urgently needed.
At the ASCO conference in 2023, Professor Christina Wu from Mayo Medical Center summarized and reported on CRC blockbuster clinical research on four new therapeutic targets of HER2 amplification, KRAS G12C mutation, NTRK fusion, and RET fusion.
HER2 amplification
MOUNTAINEER research
The study is an international, open-label phase 2 clinical study, including patients who have previously received fluorouracil, oxaliplatin, irinotecan and VEGF monoclonal antibody therapy, HER2 positive, RAS wild type, and mCRC with measurable lesions.
Initially, the study was designed as a single-cohort study, and after an interim analysis, the study cohort was expanded.
The primary endpoint was the objective response rate of cohort A and cohort B combined with blinded independent central review (BICR), and HER2-positive patients who received at least one dose of study treatment were evaluated for efficacy and safety in all patients (Figure 1).
Figure 1 MOUNTAINEER study design
The results of the study showed that the ORR of the tucatinib combined with trastuzumab group (cohort A+B) was 38.1%, and the DCR was 60%, which were significantly better than those of the tucatinib single-drug group (cohort C) (Figure 2). Median PFS was 8.2 months and median OS was 24.1 months.
Figure 2 MOUNTAINEER Study Effectiveness Results
In terms of safety, the most common adverse event in the tucatinib combined with trastuzumab group (cohort A+B group) was diarrhea, and the most common grade 3 or worse adverse event was hypertension (6/86 cases, 7%), and 3 (3%) patients experienced serious adverse events (acute kidney injury, colitis, and asthenia) related to tucatinib treatment.
No deaths due to adverse events were observed. All deaths among patients in the treatment group were attributed to disease progression.
Therefore, the researchers concluded that tucatinib combined with trastuzumab has good antitumor activity and a tolerable safety profile.
The U.S. Food and Drug Administration (FDA) approved tucatinib combined with trastuzumab for chemotherapy-refractory, HER2-positive, RAS wild-type mCRC.
MOUNTAINEER-03 Study
MOUNTAIN EER-03 is an ongoing international, open-label, phase 3 randomized controlled trial evaluating tucatinib plus trastuzumab and mFOLFOX6 versus mFOLFOX6 with or without cetuximab or Valizumab as first-line therapy in patients with HER-2-positive metastatic colorectal cancer (Fig. 3).
Figure 3 MOUNTAINEER-03 study design
In addition to the MOUNTAINEE, MOUNTAINEER-03 studies, other studies have evaluated the effectiveness of anti-HER2 therapy for HER2-positive mCRC in recent years. A summary of the efficacy and safety of these studies is shown in Figure 4.
Figure 4. Effectiveness of anti-HER2 therapy for HER2-overexpressing mCRC
KRAS G12C mutation
KRYSTAL-1 Study
This study is a phase 1b/2 cohort study, and the CRC cohort aims to evaluate the efficacy and safety of KRAS G12C inhibitor Adagasib combined with or without cetuximab in the treatment of mCRC carrying KRAS G12C mutation (Figure 5).
Figure 5 KRYSTAL-1 study CRC cohort study design
The results showed that the ORR and mDOR were significantly improved in the combined drug group (Figure 6).
Figure 6 KRYSTAL-1 Study CRC Cohort Effectiveness Results
The common side effects of the combined drug group included nausea and vomiting, diarrhea, and fatigue.
KRYSTAL-10 Study
The study is an ongoing, open-label, phase 3 study designed to evaluate the efficacy and safety of adagrasib combined with cetuximab compared with chemotherapy alone in the second-line treatment of mCRC with KRAS G12C mutation, the main study endpoint for PFS and OS.
CodeBreak100, CodeBreak101, and CodeBreak300 studies
CodeBreak100 is a phase I/II study of Sotorasib (KRAS G12C inhibitor) monotherapy in the treatment of advanced solid tumors. A total of 42 mCRC patients with KRAS G12C were enrolled in this study.
The results showed that the ORR was 7.1%, but 76.2% of the patients obtained SD, mPFS was 4 months and mOS was 10 months.
CodeBreak101 is a Phase 1b/2 clinical study evaluating the efficacy and safety of Sotarasib in combination with Panitumumab in chemotherapy-failed mCRC with KRAS G12C mutation.
As of March 25, 2022, a total of 40 patients were enrolled, the ORR was 30%, the DCR was 90%, and the mPFS was 5.7 months.
The CodeBreak300 study is an ongoing Phase 3 RCT evaluating the efficacy and safety of sotarasib plus panitumumab versus investigator’s choice of regimen in previously treated, KRAS G12C-carrying mCRC.
NTRK Fusion
Larotrectinib
Pooled analysis of phase I/II studies receiving larotrectin i b (NTRK inhibitor) monotherapy, among 159 patients, 8 patients had CRC, ORR was 50%, mDOR was 3.7 months, and the common adverse reaction was ALT Elevated, anemia, decreased neutrophil count.
Entrectinib
Combined analysis of three studies receiving Entrectinib (NTRK inhibitor) monotherapy, among 121 patients, 10 were CRC patients, ORR was 20%, mPFS was 2.8 months, mOS was 16 months, common adverse events Reactions include weight gain, anemia, and fatigue.
RET Fusion
LIBRETTO-001 Study
The study is an open-label phase 1/2 basket study evaluating the efficacy of Selpercatinib (RET inhibitor) monotherapy in RET fusion solid tumors. Ten of the included patients had CRC, with an ORR of 30% and an mDOR of 9.2 months.
Sonclusion
1. NGS testing (blood and tissue) is recommended for all mCRC patients;
2. Upcoming trials targeting the KRAS G12C mutation and other more common KRAS mutations;
3. Other targets being tested: PIK3CA, non-BRAF V600E mutations.
2023 ASCO: The research progress of 4 new targets of colorectal cancer
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