Colorectal cancer PD-1 / PD-L1 treatment

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Colon cancer immunotherapy, rectal cancer immunotherapy, colorectal cancer immunotherapy, and colorectal cancer PD-1 / PD-L1 treatment.

Seventeen years ago, the number of drugs available for advanced colorectal cancer was very limited. There were 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 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.

In 2020, what new treatment options are available for patients with colorectal cancer? What new drugs are coming to market, the Global Oncologist Network Medical Department has compiled the latest information for your reference.

Holistic drug treatment strategy for advanced colon cancer

1. First-line treatment

Treatment options for advanced colorectal cancer include chemotherapy, targeted and immunotherapy. Before the treatment, genetic testing must be carried out, because the doctor will make a treatment plan based on the location of the original lesion, genetic mutations and biomarker detection.

The chemistry of colorectal cancer usually chooses multi-drug combination. The doctors combine and match according to the actual situation of the patient. The commonly used initial standard combination scheme is as follows:

1. FOLFOX (LV / 5-fluorouracil + oxaliplatin)

2. CAPEOX (Xeloda (Capecitabine) + Oxaliplatin)

3. FOLFIRI (LV / 5-fluorouracil + irinotecan)

4. FOLFOXIRI (LV / 5-fluorouracil + irinotecan + oxaliplatin)

These treatments are usually used in combination with Avastin® (bevacizumab) to improve survival, especially for the treatment of left colon cancer.

Speaking of which, we also need to remind everyone 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. After the diagnosis, everyone must find an authoritative expert to formulate a treatment plan.

The specific plan for the left half of RAS / RAF wild-type patients is as follows. The recommended plan for Class I (preferred): FOLFOX / FOLFIRI ± Cetuximab Class II recommended plan: FOLFOX / CapeOx / FOLFIRI ± Bevacizumab; FOLFOXIRI ± Bevacizumab anti-

The specific plan for the right half of RAS / RAF wild-type patients is as follows. The recommended level I plan (preferred): FOLFOX / CapeOx / FOLFIRI ± bevacizumab; FOLFOXIRI ± bevacizumab. Compared with FOLFIRI + Avastin, FOLFOXIRI + Avastin’s 5-year overall survival rate is estimated to have doubled. Class II recommended regimen: FOLFOX / FOLFIRI ± cetuximab.

2. Second-line treatment

At the first line, we will use bevacizumab combined with chemotherapy. If the treatment is not effective, we can change the chemotherapy regimen and continue to use bevacizumab. Of course, it is also possible to change another targeted drug at the same time as a chemotherapy regimen, to change to abercept, or to ramucirumab.

3. Third-line and back-line treatment

The choice of first-line and second-line drug options for colorectal cancer is usually some relatively standard chemotherapy drugs and targeted drugs. Starting from the third-line treatment is a back-line treatment. The back-line treatment plan can use some oral chemotherapeutic drugs that have just come out, including TAS-102, as well as S-1 (tegio), rifafine, or some immunotherapy, such as pembrolizumab (MSI-H).

Advances in precise targeted therapy for colorectal cancer

In the 2017 version of the colorectal cancer treatment guidelines, the recommendations for genetic testing only involve KRAS, NRAS, dMMR and MSI-H, and in the latest treatment guidelines in 2020, new targets such as BRAF, HER2, NTRK, etc. are newly included Point, through genetic testing, to understand more molecular information of colorectal cancer, can help us find more medication options. The average survival rate of patients is more than 3 years, which is a huge progress brought by precision medicine.

1. Which genes should be tested for colorectal cancer patients

After the diagnosis, the doctor must conduct genetic testing of each patient with metastatic colorectal cancer (mCRC) as soon as possible to determine the subgroup of the disease, because this information may predict the prognosis of treatment, such as HER2 amplification suggests anti-EGFR treatment Drug resistance. The following genes must be tested!


2. Targets and targeted drugs that can currently be treated

VEGF: Bevacizumab, Apsip

VEGFR: ramucirumab, rigofinib, fruquintinib

EGFR: cetuximab, panitumumab

PD-1 / PDL-1: pamluzumab, nivolumab

CTLA-4: Ipilimumab

BRAF: Vimofinil, Connefini

NTRK: Larotinib

The list of targeted and immunotherapy drugs for colorectal cancer that have been approved so far at home and abroad:

 R & D company  Drug target  Targeted drug name  Time to market  Is China on the road
 Bristol-Myers Squibb  Her1 (EGFR / ErbB1)  Cetuximab (cetuximab)  2006  Yes
 Takeda / Amgen  Her1 (EGFR / ErbB1)  Panitumumab (panitumumab)  2005  no
 Bayer  KIT / PDGFRβ / RAF / RET / VEGFR1 / 2/3  regorafenib (regofenib)  2012  Yes
 Hutchison Whampoa  VEGFR1 / 2/3  Fruquintinib (fruquintinib)  2018  Yes
 Sanofi  VEGFR A / B  Ziv-aflibercept (Abercept)  2012  no
 Eli Lilly  VEGFR2  Ramucirumab (ramucirumab)  2014  no
 Genentech  VEGFR  Bevacizumab (bevacizumab)  2004  Yes
 Bristol-Myers Squibb  PD-1  Nivolumab (Nivolumab)  2015  Yes
 Pfizer  BRAF V600E  Encorafenib (Connefini)  2020  no
 Bristol-Myers Squibb  CTLA-4  Ipilimumab (Ipilimumab)  2011  no

Indications for colorectal cancer targeted drugs

The indications of bevacizumab  are : metastatic colorectal cancer and advanced, metastatic or recurrent non-small cell lung cancer.

The indications for trastuzumab are : HER2-positive metastatic breast cancer, HER2-positive early breast cancer, HER2-positive metastatic gastric adenocarcinoma or gastroesophageal junction adenocarcinoma patients.

The indications for Pertuzumab are : This product is suitable for combination with trastuzumab and chemotherapy as an adjuvant treatment for patients with high-risk recurrence of HER2-positive early breast cancer.

The indications of Nivolumab are : epidermal growth factor receptor (EGFR) gene mutation negative and anaplastic lymphoma kinase (ALK) negative, previous disease progression or intolerable locally advanced or metastatic after receiving platinum-based chemotherapy Adult patients with non-small cell lung cancer (NSCLC).

The indications of regorafenib are : patients with previously treated metastatic colorectal cancer. Durvalumab, Tremelimumab, Ipilimumab, and lapatini
b are not yet available in China.

EGFR gene mutation

Epidermal growth factor receptor (EGFR) occurs in about 10% of colon cancers, most commonly on the left.

Cetuximab and panitumumab were officially approved by the FDA in 2004 and 2006 for the treatment of advanced colorectal cancer.

Drug name: panitumumab (Vectibix)

Target: EGFR

Manufacturer: Amgen (outside)

Indications: EGFR positive colorectal cancer, KRAS negative colorectal cancer

Drug name: Cetuximab (Erbitux)

Target: EGFR

Manufacturer: Merck (outside)

Indications: advanced colorectal cancer, head and neck cancer

BRAF V600E gene mutation

7-10% of colon cancer patients carry BRAF V600E mutation. The BRAF V600E mutation is a BRAF activating mutation and is the variant with the highest proportion of BRAF.

Has unique clinical characteristics:

Mainly appears in the right colon;

The proportion of dMMR is high, reaching 20%;

Poor prognosis of BRAF V600E mutation;

Atypical transfer mode;

Patients with BRAF mutant genes usually have a poor prognosis, and some new precise anti-cancer drugs have been shown to double survival time.

The study found that FOLFOXIRI + bevacizumab may become the best treatment for patients with BRAF mutations.

The NCCN guidelines for version V2 2019 recommend the second-line treatment of metastatic colorectal cancer for BRAF V600E:

Verofenib + irinotecan + cetuximab / panitumumab

Dabarafenib + Trametinib + Cetuximab / Panitumumab

Encorafenib + Binimetinib + Cetux / Pan

The good news is that in the face of such a dangerous BRAF V600E mutant metastatic colorectal cancer, on April 8, 2020, Pfizer announced that the US FDA has approved Braftovi® (encorafenib, Cornefinil) and Erbitux® (cetuximab) , Cetuximab) combined drug regimen (Braftovi second drug regimen), used to treat patients with metastatic colorectal cancer (mCRC) carrying BRAF V600E mutation. These patients have already received one or two pre-treatments. This approval also makes the Braftovi second drug regimen the first targeted therapy approved by the FDA for patients with mCRC carrying BRAF mutations.

Kras gene mutation

KRAS wild-type colon cancer is the first-line treatment of choice for targeted combination chemotherapy, so what kind of chemotherapy option to choose?

While choosing a certain targeted drug, it is recommended to choose a chemotherapy regimen with a longer OS, that is, cetuximab should be combined with FOLFOX, and bevacizumab should be combined with FOLFIRI. The specific choice of plan needs to be combined with clinical specific analysis:

If there is hope for cure, cetuximab combined with chemotherapy is generally preferred, because the recent objective efficiency of cetuximab is higher than bevacizumab;

For patients with advanced incurable disease, bevacizumab combined with chemotherapy can be used as the first line, followed by cetuximab or panitumumab.

Patients with metastatic colon cancer should be tested for RAS mutation status including KRAS and NRAS. At least the status of KRAS exon 2 should be determined.

If conditions permit, KRAS exon 2 exon and NRAS mutation status need to be clarified.

Bevacizumab combined with two-drug chemotherapy can bring PFS (median progression-free survival) and OS (overall survival) benefits to patients with KRAS mutations.

For patients with RAS mutations, the use of cetuximab may have a negative impact on the overall efficacy.

Patients with KRAS mutations or NRAS mutations should not use cetuximab or panitumumab.

HER2 amplification

HER2 amplification or overexpression was found in 2% to 6% of patients with advanced or metastatic colorectal cancer.

Pertuzumab and trastuzumab combine with different HER2 domains to produce synergistic inhibition on tumor cells.

My Pathway is the first clinical study to explore the efficacy of Pertuzumab + Trastuzumab therapy in patients with HER2 amplified metastatic colorectal cancer (regardless of KRAS mutation status). This study shows that HER2 dual-targeted therapy-Pertuzumab + Trastuzumab is well tolerated, or may be used as a treatment plan for patients with HER2 amplified metastatic colorectal cancer. Early genetic testing to identify HER2 mutations and consider early use of HER2 targeted therapy may benefit patients.

NTRK gene fusion mutation

About 1 to 5% of colon cancer patients develop NTRK fusion, and NGS testing is recommended.

From January 23 to January 25, 2020, the American Society of Clinical Oncology Gastrointestinal Tumor Symposium (ASCO-GI) specifically analyzed the clinical drug effects of patients with gastrointestinal tumors carrying NTRK fusion protein.

The test results showed that the overall remission rate of the gastrointestinal cancer subgroup was 43%, and the overall remission rate of colon cancer patients was 50%. The duration of the response varies greatly, from 3.5 months to more than 14.7 months.

After a median follow-up period of 19 months, the median overall survival time was up to 33.4 months, nearly three years. The one-year overall survival rate (OS) is 69%. At the time of the data cutoff, four colon cancer patients and one pancreatic cancer patient were still alive and their condition did not deteriorate. And the safety and tolerability of larotinib is good. Most adverse reactions are grade 1 or 2.

A 75-year-old woman with metastatic colorectal cancer (CRC) is very lucky:

Primary colon tumor.

Peritoneal cancer.

Liver metastasis.

Entratinib 1600mg / m 2 was taken orally once a week once a week for 4 consecutive days (i.e. 4 days / 3 days off), every 28 days for three consecutive weeks. After eight weeks of treatment, the lesion was significantly reduced.

Colorectal cancer immunotherapy and new breakthrough inventory

Prognostic order: MSI-H and BRAF wild type> MSI-H and BRAF mutant> MSS and BRAF wild type> MSS and BRAF mutant.

1. MSI-H / dMMR metastatic colorectal cancer

High microsatellite instability (MSI-H) is a good prognostic factor, and the rate of BRAF mutation in MSI-H colorectal cancer is about 50%.

Immune checkpoint inhibitors are an effective treatment for MSI-H. The immune checkpoint inhibitors currently applicable to patients with MSI-H type mCRC include pembrolizumab, nivolumab, and ipilimumab.

Nivolumab / Ipilimumab combination shows strong activity in first-line treatment

The front-line combination of nivolumab (Opdivo) and ipilimumab (Yervoy) has shown a strong and long-lasting clinical benefit in patients with metastatic colorectal cancer (mCRC), and its tumor is microsatellite instability (MSI-H) / mismatch repair Defect (dMMR) -a FACP Heinz-Josef Lenz, MD, said people with a poor prognosis history.

In the Phase II CheckMate-142 trial, the researchers examined the safety and efficacy of nivolumab plus low-dose ipilimumab as first-line treatment for patients with MSI-H / dMMR mCRC (n = 45). Previous results submitted at the 2018 ESMO conference showed that the overall response rate (ORR) of 45 patients was 60%, and the disease control rate was 84%. At the 2019 ASCO Annual Meeting, the clinical update of the trial was announced. At a median follow-up time of 19.9 months, the ratio of ORR to combination assessed by the investigator increased to 64%, and 84% of patients had disease control for ≥12 weeks.

2. MSS colorectal cancer

New breakthrough in MSS colorectal cancer: regorafen
ib (Stivarga) + nivolumab

For a patient with microsatellite stabilization (MSS) disease, about 53 patients received [combination therapy] and achieved a high response rate of 40%, which is unheard of in this part of refractory patients.

There are persistent data suggesting that anti-VEGF therapy may have a synergistic effect with PD-1 blockade. Now, this is the first time among the MSS population. By combining these two treatment strategies, we have seen very impressive results. Therefore, by combining anti-VEGF strategies with immune checkpoint suppression, patients with MSS disease will have greater survival benefits.

Article conclusion

In the era of targeted therapy, every patient with colorectal cancer should pass MSI detection, mutation analysis of RAS and BRAF, and perform HER2 amplification, NTRK and other gene detection as far as possible. Genetic testing (NGS) will be included in the large The initial examination standard for most patients. Now domestic patients can be tested through the Global Oncologist Network.

We live in the molecular revolution of colorectal cancer treatment. We have learned a lot about the molecular genetics of colon cancer and how to translate it into clinical treatment decisions. There will be more in the future. As for the latest research progress and the best medication plan for colorectal cancer, only the top cancer experts at home and abroad have rich clinical experience. Colorectal cancer patients can apply for consultation with authoritative experts through the Global Oncologist Network to obtain the best treatment plan.

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