Thank you so much everyone. It fills my heart with joy to talk to you all about promising molecular targets and the role of next-generation sequencing in early-phase drug development in colorectal cancer. Again, I’m Vivek Subbiah, and I’m available on Twitter and BlueSky. We are in an era of precision oncology, moving away from diagnosis via light microscope to a molecular microscope. What do I mean by a molecular microscope? Next-generation sequencing.
Twenty years ago, sequencing the human genome was considered impossible. It took $3 billion to sequence it. Today, it can be done for a few hundred to a few thousand dollars, depending on where you are. We’re living in an era where molecular profiling is routine and affordable.
The future is the AI era microscope, where artificial intelligence will help us amalgamate all the data we have—medical records, genomics, proteomics, spatial transcriptomics, and everything else—to provide precision therapies.
We’re also evolving toward tissue-agnostic drug development, moving away from one-size-fits-all chemotherapy to histology-dependent targeted therapy and now to tissue-agnostic therapies. There’s a commentary in Nature that says we should forget naming cancers as lung, breast, prostate, or colorectal cancers. Instead, we should think about molecular targets. The old way of classifying cancers by origin is delaying access to drugs for patients who could benefit from them.
So what are tissue-agnostic therapies? These therapies treat cancers based on molecular alterations, not the tumor’s origin. For example, we now have around 10 approved tissue-agnostic drugs, including pembrolizumab for DMMR-positive cancers, three drugs for NTRK fusion-positive cancers (larotrectinib, entrectinib, and repotrectinib), dabrafenib and trametinib for BRAF V600E-positive cancers, selpercatinib for RET fusions, and HER2-targeted therapies like trastuzumab deruxtecan. Colorectal cancer has benefited significantly from these advances.
Colorectal cancer is now divided into subtypes based on molecular pathways such as the conventional pathway, the serrated pathway, and the alternative pathway. These classifications depend on markers like MSI status, BRAF mutations, RAS mutations, HER2 amplification, and others. In metastatic colorectal cancer, treatment decisions are based on patient characteristics, tumor characteristics, and molecular profiling such as RAS, BRAF, HER2, and MSI high status.
Let’s dive into the clinical trials shaping the treatment landscape.
The BEACON study combines encorafenib (a BRAF inhibitor) and cetuximab (an EGFR inhibitor) with or without binimetinib (a MEK inhibitor). Results show improved survival and response rates in BRAF V600E-positive colorectal cancer compared to standard therapies.
The Breakwater study examines encorafenib with EGFR inhibitors and chemotherapy as first or second-line therapy for BRAF-mutant colorectal cancer. Immunotherapies like nivolumab and ipilimumab or pembrolizumab are now first-line treatments for MSI-high colorectal cancer. Studies show significantly better progression-free survival compared to chemotherapy.
HER2-targeted therapies are also making strides. The Mountaineer study combines tucatinib and trastuzumab for HER2-positive colorectal cancer and shows a 38.1% response rate. The Destiny study uses trastuzumab deruxtecan (Enhertu) with a 46.9% response rate in HER2 IHC 3+ colorectal cancer. Emerging therapies for colorectal cancer include KRAS inhibitors. Adagrasib combined with cetuximab for KRAS G12C mutations achieved a 34% response rate with 6.9 months progression-free survival. Emerging drugs target KRAS G12D, G12V, and pan-KRAS mutations, along with KRAS degraders and protacs.
Antibody-drug conjugates are showing promising results as well. C-MET ADCs such as AbbVie 400 show activity in late-line metastatic colorectal cancer. CCAM5 ADCs are also showing early efficacy in trials. Tissue-agnostic fusion therapies are another area of interest. NTRK fusions treated with larotrectinib achieve a 50% response rate in colorectal cancer, while RET fusions treated with selpercatinib achieve a 20% response rate.
Dr. Subbiah concludes by stressing the importance of comprehensive molecular profiling. This involves genomics, immunogenomics, metabolomics, proteomics, and transcriptomics to create a detailed molecular portrait for each patient. Universal molecular testing, including germline testing, is essential for advancing treatment in metastatic colorectal cancer. Current and emerging therapies, such as MSI-H checkpoint inhibitors, HER2-targeted ADCs, and KRAS inhibitors, are transforming colorectal cancer treatment and providing hope for improved outcomes through personalized medicine.