Small and strong
Colorectal cancer (CRC) is the third most common malignancy in the world. Chemotherapy is the cornerstone of CRC, but its clinical application is limited by inevitable resistance, narrow mechanism of action, and adverse effects. There are few options after chemotherapy resistance, and there is an urgent need for an efficient and tolerable regimen.
At the 2023 ASCO Conference, Professor Christina Wu from Mayo Clinic summarized the major clinical studies of CRC in four novel therapeutic targets: HER2 amplification, KRAS G12C mutation, NTRK fusion, and RET fusion.
HER2 amplification
01MOUNTAINEER RESEARCH
The study was an international, open-label, Phase 2 clinical study that included prior 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 interim analysis, the study cohort was expanded. The primary endpoint was objective response rates for cohort A and Cohort B in combination with blinded independent central review (BICR) and efficacy and safety assessment in all HER2-positive patients who received at least one dose of study therapy (figure 1).
FIGURE 1 MOUNTAINEER STUDY DESIGN
The results showed an ORR of 38.1% and a DCR of 60% in the tucardinib plus trastuzumab group (cohort A+B), significantly better than the tucatinib monotherapy group (cohort C) (figure 2). The median PFS was 8.2 months and the median OS was 24.1 months.
FIGURE 2 MOUNTAINEER STUDY EFFECTIVENESS RESULTS
In terms of safety, the most common adverse event in the tucatinib plus trastuzumab group (cohort A+B) was diarrhoea, the most common grade 3 or more adverse event was hypertension (6/86 patients, 7%), and serious adverse events (acute kidney injury, colitis, and frailty) associated with tucatinib treatment in 3 patients (3%). No deaths due to adverse events were observed. All deaths in the treatment group were attributed to disease progression.
From this, the researchers concluded that tucatanib in combination with trastuzumab has good antitumor activity and is well tolerated. The US Food and Drug Administration (FDA) approved tucatinib in combination with trastuzumab for chemotherapy-refractory, HER2-positive, RAS wild-type mCRC.
02MOUNTAINEER-03 STUDY
MOUNTAINEER-03 is an ongoing international, open-label, phase 3 randomized controlled trial evaluating the first-line treatment of tucatanib plus trastuzumab and mFOLFOX6 versus mFOLFOX6 with or without cetuximab or bevacizumab in patients with HER-2-positive metastatic colorectal cancer (figure 3).
Figure 3 MOUNTAINEER-03 study design
In addition to the MOUNTAINEE, MOUNTAINEER-03 studies, other studies have evaluated the efficacy of anti-HER2 therapy for HER2-positive mCRC in recent years. A summary of the effectiveness and safety of these studies is shown in Figure 4.
Figure 4 Effectiveness of anti-HER2 therapy for HER2 overexpression of mCRC
KRAS G12C mutation
01KRYSTAL-1 STUDY
This is a phase 1b/2 cohort study designed to evaluate the efficacy and safety of the KRAS G12C inhibitor Adagasib with or without cetuximab in the treatment of mCRCs carrying the KRAS G12C mutation (figure 5).
Figure 5 KRYSTAL-1 study CRC cohort study design
Results showed significant improvements in ORR and mDOR in the combination group (Figure 6).
Figure 6 KRYSTAL-1 Study CRC Cohort Effectiveness Results
Common side effects in the combination group included nausea, vomiting, diarrhea, and fatigue.
02KRYSTAL-10 RESEARCH
This is an ongoing, open-label, phase 3 study to evaluate the efficacy and safety of Adagrasib plus cetuximab versus chemotherapy alone for second-line treatment of mCRC with KRAS G12C mutations, with primary endpoints of PFS and OS.
03 CodeBreak100, CodeBreak101 and CodeBreak300 studies
CodeBreak100 is a phase I/II study of Sotorasib (KRAS G12C inhibitor) monotherapy for advanced solid tumors, which enrolled a total of 42 patients with mCRC with KRAS G12C and showed an ORR of 7.1%, but 76.2% achieved SD, mPFS for 4 months, and mOS for 10 months.
CodeBreak101 A Phase 1b/2 clinical study evaluating the efficacy and safety of Sotarasib in combination with Panitumumab in the treatment of mCRCs that have failed chemotherapy and carry the KRAS G12C mutation. As of 25 March 2022, a total of 40 patients were enrolled with an ORR of 30%, a DCR of 90%, and an mPFS of 5.7 months.
The CodeBreak300 study is an ongoing Phase 3 RCT evaluating the efficacy and safety of Sotarasib plus Panitumumab compared with investigator-selected regimens for previously treated mCRC carrying KRAS G12C.
NTRK fusion
01Larotrectinib
In a phase I/II study of Larotrectinib (NTRK inhibitor) monotherapy, 8 of 159 patients had CRC, an ORR of 50%, and an mDOR of 3.7 months, with common adverse effects being elevated ALT, anaemia, and decreased neutrophil count.
02Entrectinib
In a pooled analysis of three studies receiving Entrectinib (NTRK inhibitor) monotherapy, 10 of 121 patients were CRC patients with an ORR of 20%, mPFS was 2.8 months, and mOS was 16 months, with common adverse effects such as weight gain, anaemia, and fatigue.
RET fusion
01LIBRETTO-001 STUDY
The study was an open-label, phase 1/2 basket study evaluating the effectiveness of Selpercatinib (RET inhibitor) monotherapy for RET-fused solid tumors. Ten of the included patients were CRC patients with an ORR of 30% and an mDOR of 9.2 months.
Conclusion 1: NGS testing (blood and tissue) is recommended for all patients with mCRC; 2. Upcoming tests targeting the KRAS G12C mutation and other more common KRAS mutations; 3. Other targets under trial: PIK3CA, non-BRAF V600E mutation.