Colorectal cancer PD-1 / PD-L1 treatment

Seventeen years ago, the number of drugs available for advanced colorectal cancer was very limited — only a few chemotherapeutic drugs and almost no targeted drugs. With the development of genomic testing and sophisticated cancer drugs, patients diagnosed with stage IV colon cancer now have more and more treatment options. Some patients can achieve clinical cure, while others can obtain more targeted immunotherapy options through genetic testing, resulting in longer survival time. At present, the survival time of advanced colorectal cancer has increased from less than one year to 3 years, and 20% of patients can survive for 5 years or longer.

Treatment options for advanced colorectal cancer include chemotherapy, targeted therapy, and immunotherapy, and genetic testing must be carried out before treatment begins, as doctors formulate treatment plans based on the location of the original lesion, genetic mutations, and biomarker detection. It is also important to note that the treatment plan and prognosis of colorectal cancer tumors occurring on the left side (descending colon, sigmoid colon, rectum) and right side (ascending colon, transverse colon, cecum) are completely different and should not be confused.

The chemotherapy for colorectal cancer usually involves multi-drug combinations. The commonly used initial standard combination schemes include FOLFOX (LV/5-fluorouracil + oxaliplatin), CAPEOX (Capecitabine + Oxaliplatin), FOLFIRI (LV/5-fluorouracil + irinotecan), and FOLFOXIRI (LV/5-fluorouracil + irinotecan + oxaliplatin). These are often used in combination with Avastin (bevacizumab) to improve survival, especially for left colon cancer. For RAS/RAF wild-type patients with left-sided tumors, the preferred Class I regimen is FOLFOX/FOLFIRI ± Cetuximab, while for right-sided tumors, FOLFOX/CapeOx/FOLFIRI ± bevacizumab or FOLFOXIRI ± bevacizumab is preferred — with FOLFOXIRI + Avastin estimated to have doubled the 5-year overall survival rate compared to FOLFIRI + Avastin.

For second-line treatment, if bevacizumab combined with chemotherapy fails at first line, the chemotherapy regimen can be changed while continuing bevacizumab, or switched to abercept or ramucirumab alongside a new chemotherapy regimen. For third-line and beyond, treatment options include oral chemotherapeutic drugs such as TAS-102 and S-1, as well as immunotherapy such as pembrolizumab for MSI-H patients.

In the 2020 treatment guidelines, new targets such as BRAF, HER2, and NTRK have been added beyond the previously recommended KRAS, NRAS, dMMR, and MSI-H. Every patient with metastatic colorectal cancer (mCRC) must undergo genetic testing as soon as possible after diagnosis to determine disease subgroup, as this information predicts prognosis and guides treatment selection. The genes that must be tested include MSI, BRAF, KRAS, NRAS, RAS, HER2, and NTRK.

Currently actionable targets and their corresponding drugs include VEGF (bevacizumab, aflibercept), VEGFR (ramucirumab, regorafenib, fruquintinib), EGFR (cetuximab, panitumumab), PD-1/PD-L1 (pembrolizumab, nivolumab), CTLA-4 (ipilimumab), BRAF (vemurafenib, encorafenib), and NTRK (larotrectinib). Cetuximab and panitumumab were officially approved by the FDA in 2004 and 2006 respectively for the treatment of advanced colorectal cancer targeting EGFR, which occurs in about 10% of colon cancers, most commonly on the left side.

For KRAS wild-type colon cancer, cetuximab should be combined with FOLFOX and bevacizumab with FOLFIRI. Patients with KRAS or NRAS mutations should not use cetuximab or panitumumab, as it may negatively impact overall efficacy. Bevacizumab combined with two-drug chemotherapy can bring progression-free survival and overall survival benefits to patients with KRAS mutations.

For BRAF V600E mutations, which are found in 7–10% of colon cancer patients and carry a poor prognosis, FOLFOXIRI + bevacizumab may be the best treatment option. The NCCN guidelines recommend second-line treatment combinations such as encorafenib + binimetinib + cetuximab/panitumumab. In April 2020, the FDA approved Braftovi (encorafenib) in combination with Erbitux (cetuximab) as the first targeted therapy approved specifically for patients with mCRC carrying BRAF V600E mutations who have received one or two prior treatments.

HER2 amplification or overexpression is found in 2% to 6% of patients with advanced or metastatic colorectal cancer. The My Pathway clinical study demonstrated that HER2 dual-targeted therapy combining pertuzumab and trastuzumab is well tolerated and may serve as a viable treatment plan for patients with HER2-amplified mCRC, making early genetic testing to identify HER2 mutations particularly important.

For NTRK gene fusion mutations, which occur in about 1–5% of colon cancer patients, NGS testing is recommended. Data presented at the 2020 ASCO Gastrointestinal Tumor Symposium showed that the overall remission rate in colon cancer patients with NTRK fusions was 50%, with a median overall survival of 33.4 months and a one-year overall survival rate of 69%. The safety and tolerability of larotrectinib were good, with most adverse reactions being grade 1 or 2.

The prognostic order for colorectal cancer based on molecular subtype is as follows: MSI-H with BRAF wild type carries the best prognosis, followed by MSI-H with BRAF mutation, then MSS with BRAF wild type, and MSS with BRAF mutation carries the poorest prognosis.

For MSI-H/dMMR metastatic colorectal cancer, immune checkpoint inhibitors are an effective treatment. The rate of BRAF mutation in MSI-H colorectal cancer is approximately 50%. Applicable immune checkpoint inhibitors include pembrolizumab, nivolumab, and ipilimumab. In the Phase II CheckMate-142 trial evaluating nivolumab plus low-dose ipilimumab as first-line treatment for MSI-H/dMMR mCRC patients, the overall response rate assessed by investigators was 64% at a median follow-up of 19.9 months, with 84% of patients achieving disease control for 12 weeks or longer — demonstrating strong and durable clinical benefit in a patient population with historically poor prognosis.

For microsatellite stable (MSS) colorectal cancer, which has historically shown limited response to immunotherapy, a new breakthrough has emerged in the combination of regorafenib (Stivarga) and nivolumab. Among approximately 53 patients with MSS disease who received this combination therapy, a response rate of 40% was achieved — a result previously unheard of in this refractory patient population. The rationale lies in evidence suggesting that anti-VEGF therapy may have a synergistic effect with PD-1 blockade, and by combining these two strategies, patients with MSS disease are now showing significantly greater survival benefits than with either approach alone.

In the era of targeted therapy, every colorectal cancer patient should undergo MSI detection, RAS and BRAF mutation analysis, and HER2 amplification and NTRK gene testing wherever possible. Next-generation sequencing (NGS) is expected to become a standard part of the initial workup for the majority of colorectal cancer patients, as precision medicine continues to transform treatment decisions and extend survival in this disease.