Although the application of immunotherapy in lung cancer in the past two years has become more and more extensive, the status of targeted therapy can not be shaken. In the first edition of the NCCN Guidelines in 2022, there have been a number of updates to the Targeted Therapy chapter. The new guidelines recommend broader molecular testing for metastatic NSCLC. In addition to classical targets, attention should also be paid to the detection of emerging biomarkers.
Classic targets recommended by the guide include—
EGFR 19 exon deletion mutation (Del19) or L858R mutation, EGFR S768I, L861Q and/or G719X mutation, EGFR 20 exon insertion mutation (EGFR ex20ins), KRAS G12C mutation, ALK rearrangement, ROS1 rearrangement, BRAF V600E mutation, NTRK1/2/3 fusion, MET14 jump mutation, RET rearrangement, and PD-L1.
New targets recommended by the guidelines include—
High levels of MET amplification and ERBB2 (HER2) mutations.
Today's focus is on her2 mutations and the drugs that target this target.
HER2 is a common oncogene. Many cancer types are overexpressed, such as stomach cancer, breast cancer and so on. Between 15% and 25% of patients with new-onset breast cancer have HER2 gene amplification or protein overexpression. HER2-positive breast cancer is an aggressive cancer with a worse prognosis than her2-normal breast cancer. Similarly, there are quite a few urothelial cancers that are HER2 positive. In lung cancer, HER2 mutations are rare mutations, accounting for about 2% to 4% of non-small cell lung cancers, mainly in women, non-smoking and lung adenocarcinoma patients.
The treatment recommendations for two antibody-conjugated drugs (ADCs) T-DM1 and T-DXd are added to the 2022 NCN guidelines for lung cancer.
1.T-DM1
T-DM1 is an antibody-drug conjugate that conjugates the anti-HER2 monoclonal antibody herceptin to the chemotherapy drug methenin, a coupling structure that allows the drug to be released locally in tumor cells to exert anti-tumor effects. A US study showed that T-DM1 treated 44% of 18 patients with HER2 mutation NSCLC and 55% of T-DXd treated 91 patients with HER2 mutation NSCLC, with a median response duration (DoR) of 9.3 months, a median PFS of 8.2 months, and a median total survival (OS) of 17.8 months.
2.T-DXd
T-DXd, also known as DS-8201, is a novel anti-HER2 antibody conjugated drug (ADC), composed of anti-HER2 humanized monoclonal antibody and DXd, the antibody part of the amino acid sequence is the same as trastuzumab, DXd has higher anti-tumor activity than irinotecan, T-DXd peptide linker is stable in plasma, adheres to tumor cells and internalizes, peptide linkers are lysed by lysosomal enzymes and released DXd. In addition, T-DXd also has an effect on HER2-negative cells adjacent to HER2-positive tumor cells. Compared to TDM-1, T-DXd has a higher drug-to-antibody ratio, delivering more efficiently to tumor cells expressing HER2.
The DESTINY-Lung01 study showed that the ORR of patients with HER2 mutation-positive non-small cell lung cancer who was treated posteriorly with T-DXd could reach 61.9%, and the median PFS was 14 months, all of which were higher than the previous drugs.
T-DM1 has been listed in China, but the current CSCO guidelines recommend adjuvant therapy for patients with HER2-positive early-stage breast cancer, which is not recommended in lung cancer, while T-DXd has not yet been listed in China, and many clinical trials are currently underway.