What Are the Uses of Carboplatin and Pemetrexed?

Many cancers can be reclassified according to molecular criteria or genomic abnormalities, such as non-small cell lung cancer. 80% of global diagnosis of lung cancer is non-small cell lung cancer (closely related to genetic mutations) and 20% is small cell lung cancer (closely related to smoking). And> 50% of non-small cell lung cancers are diagnosed in advanced stages (lymph node invasion or metastasis). The use of genomic analysis in diagnosis is increasingly helpful to provide information. The choice of treatment can be based on molecular or genomic changes, and targeted therapeutic drugs for different gene targets are more beneficial to patients to obtain significant curative effects.

Individualized treatment of tumor

Many cancers can be reclassified according to molecular criteria or genomic abnormalities, such as non-small cell lung cancer. 80% of global diagnosis of lung cancer is non-small cell lung cancer (closely related to genetic mutations) and 20% is small cell lung cancer (closely related to smoking). And> 50% of non-small cell lung cancers are diagnosed in advanced stages (lymph node invasion or metastasis). The use of genomic analysis in diagnosis is increasingly helpful to provide information. The choice of treatment can be based on molecular or genomic changes, and targeted therapeutic drugs for different gene targets are more beneficial to patients to obtain significant curative effects.

Chinese name

Individualized treatment of tumor

According to

Characteristics of pharmacogenomics

Advantage

Save valuable treatment time

Suitable for the crowd

In patients with non-small cell lung cancer with adenocarcinoma

Detection method

Fluorescence in situ hybridization (FISH)

Discovery of oncogenic driver ALK

EML4-ALK fusions occur in approximately 3-5% of non-small cell lung cancers, depending on the population studied and the ALK detection method used [1].

EML4-ALK is a driver mutation in non-small cell lung cancer

In 2007, two independent research groups identified ALK gene rearrangements in non-small cell lung cancer.

One group of researchers has developed a retroviral cDNA expression library to screen for new oncogenes. They transfected a cDNA library extracted from a lung adenocarcinoma of a 62-year-old Japanese male smoker who had been negatively screened for KRAS and EGFR mutations, and designed to generate transgenic mice that specifically express EML4-ALK in alveolar cells. This produced many lung adenocarcinoma nodules. Treatment of these transgenic mice with ALK inhibitors resulted in reduced tumor burden compared to untreated mice. Most mice died quickly within 1 month. Treatment with the same ALK inhibitor resulted in lung infiltration without EML4-ALK / 3T3 cells and prolonged survival. This study strongly confirms that EML4-ALK is a driver mutation in non-small cell lung cancer, and that inhibition of EML4-ALK activity in vivo leads to reduced lung cancer burden ^[1]

The current draft version of the guidelines from the CAP, the International Association for the Study of Lung Cancer, and the Molecular Pathology Association recommends that ALK testing be performed in all patients with non-small cell lung cancer exhibiting an adenocarcinoma component, regardless of age, race, gender, and smoking history. The current National Comprehensive Cancer Network guideline recommendations developed by the Expert Opinion Group reflect the detection of all adenocarcinomas, large cell and non-small cell lung cancers without specific EGFR mutations and ALK gene rearrangements, with crizotinib as ALK First-line treatment of gene rearrangement in non-small cell lung cancer ^[1]

A large amount of clinical data shows that the mRNA expression levels of target genes such as ERCC1 / RRM1 / TYMS / TUBB3 in tumor tissues can predict patients' common use of platinum, gemcitabine, fluorouracil, and anti-microtubules.

ALK gene target detection method

Fluorescence in situ hybridization

ALK separation and fluorescence in situ hybridization detection ^[2]

Chemotherapy is a method of treating cancer with drugs. These drugs are often called chemotherapeutics or anticancer drugs and can directly destroy and kill cancer cells. In the past 50 years, due to the rapid development of anti-tumor drug treatment and the update of clinical treatment concepts, chemotherapy has achieved many significant results, becoming one of the methods of radical tumor treatment, and an indispensable important method in the comprehensive treatment of common tumors.

Effectiveness of chemotherapy in individualized treatment of tumor

Not necessarily! Clinical results show that only 30 to 40 percent of patients benefit from each chemotherapy regimen. The efficacy of chemotherapy is related to the individual differences of patients (the patient's sensitivity to the chemotherapy drug and the tolerance of the drug) and the toxic response of the drug itself. Therefore, chemotherapy for tumors needs to consider the mutually restrictive relationship between drugs, tumors and individuals. It is impractical to increase the efficacy by simply increasing the dose of the drug. The worsening of the drug's toxic response will force the doctor to delay or stop chemotherapy. Selecting drugs for tumor chemotherapy based on clinical experience alone is often not efficient.

Tumor personalized medicine treatment

In recent years, with the development of molecular biology technology and the further understanding of the pathogenesis from the cellular and molecular level, the development of tumor targeted therapy has entered a new era. Progress in these areas has been rapid and good results have been achieved in the clinic. According to the targets and properties of the drugs, the drugs targeted for the main molecular therapy can be divided into the following categories:

1. Targeted epidermal growth factor receptor (EGFR) blockers, such as Gefitinib (Iressa); Erlotinib (Tareva);

2. Tyrosine kinase receptor inhibitors, such as Crizotinib (Xalkori®) targeting molecules include ALK, hepatocyte growth factor receptor (HGFR, c-Met) and RON. Translocation can promote the expression of oncogenic fusion protein by ALK gene. The formation of ALK fusion proteins can cause the activation and deregulation of gene expression and signals, which in turn promote the proliferation and survival of tumor cells expressing these proteins. Crizotinib has a concentration-dependent inhibition of the phosphorylation of ALK and c-Met at the cellular level in tumor cell lines, and has xenograft-bearing tumors expressing EML4-ALK or NPM-ALK fusion protein or c-Met Mice have antitumor activity.

3. Monoclonal antibodies against certain specific cell markers, such as Cetuximab (Erbitux); monoclonal antibodies against HER-2, such as Herceptin (Trastuzumab, Herceptin);

4 Bcr-Abl tyrosine kinase inhibitors, such as Imatinib and Dasatinib;

5. Vascular endothelial growth factor receptor inhibitors, such as Bevacizumab (Avastin);

6. Anti-CD20 monoclonal antibodies, such as Rituximab;

7. IGFR-1 kinase inhibitors, such as NVP-AEW541;

8. mTOR kinase inhibitors, such as CCI-779;

9. Ubiquitin-proteasome inhibitors, such as Bortezomib;

10 Others, such as Aurora kinase inhibitors, histone deacetylase (HDACs) inhibitors, etc.

Clinical research

Study 1001 (crizotinib objective response rate of 61%)

At the time of the lock-in analysis of study A8081001 as of September 2010, 119 patients with ALK-positive locally advanced or metastatic non-small cell lung cancer were evaluated. Their average treatment cycle was 32 weeks. According to the researcher's assessment, there were 2 patients with complete remission and 69 patients with partial remission, with an objective response rate of 61% (95% CI: 52%, 70%). During the first 8 weeks of treatment, the objective tumor response rate was 55%. The median duration of remission was 48.1 weeks.

Study 1005 (crizotinib objective response rate is 50%)

At the time of the lock-up analysis of study A8081005 as of September 2010, 136 patients with ALK-positive locally advanced or metastatic non-small cell lung cancer were evaluated. Their average treatment period is 22 weeks. According to the researcher's assessment, one patient had a complete response and 67 patients had a partial response, with an objective response rate of 50% (95% CI: 42%, 59%). During the first 8 weeks of treatment, the objective tumor response rate was 79%. The median duration of remission was 41.9 weeks.

As part of the PROFILE 1005 test, the ALK fluorescence in situ hybridization assay has been validated in pathological specimens, which is also a clinically validated ALK detection method ^[1] .

Study A8081005 is still ongoing and is expected to be completed in the third quarter of 2013.

Crizotinib was approved in the United States on August 26, 2011, mainly based on the 50% response rate of 136 ALK-rearranged non-small cell lung cancer patients first selected by PROFILE1005, followed by 119 among the first selected by PROFILE 1001 The response rate of ALK gene rearrangement in non-small cell lung cancer patients was 61%.

PROFILE107 is a non-placebo controlled trial of crizotinib and standard chemotherapy (pemetrexed or docetaxel) in patients with ALK-positive non-small cell lung cancer. All 347 patients have received first-line chemotherapy. PROFILE 1007 trial data have been published at the European Society of Oncology (ESMO) 2012. The results showed that the median progression-free survival (PFS) of the crizotinib group was 7.7 months, compared with a median of 3.0 months for patients receiving chemotherapy (HR 0.49, 95% CI 0.37-0.64, P < 0.0001), and the total effective rate of crizotinib was also significantly higher (65% vs. 20%, P <0.0001). ^[4]

Other related research

Study A8081014 is a randomized, controlled, open phase III study comparing oral crizotinib with pemetrexed / cisplatin, or pemetrexed / carboplatin first-line chemotherapy at a starting dose of 250 mg BID Safety and effectiveness of advanced ALK-positive non-squamous non-small cell lung cancer. A total of 334 patients were planned to be randomly assigned in a 1: 1 ratio to either group A (crizotinib ) or group B (chemotherapy: pemetrexed / cisplatin or pemetrexed / carboplatin). As of November 2012, a total of 261 patients have been randomized. It is expected to be completed in the fourth quarter of 2015.

Study A8081029 is an ongoing multicenter, randomized, controlled, open phase III study comparing crizotinib with chemotherapy in previously untreated East Asian ALK-positive advanced non-squamous non-small cell lung cancer patients ( Ie pemetrexed / cisplatin or pemetrexed / carboplatin). Patients were enrolled from China, Taiwan, Hong Kong, Thailand and Malaysia. The 200 patients planned to be enrolled were randomly assigned in a 1: 1 ratio to group A (crizotinib ) or group B (chemotherapy: pemetrexed / cisplatin or pemetrexed / carboplatin). Of these, 150 patients were from China, while the remaining 50 patients were from other Asian countries. It is expected to be completed in the fourth quarter of 2015.