What are the individualized treatments for HER2-mutant non-small cell lung cancer?

When it comes to epidermal growth factor receptor 2 (ERBB2, HER2), the first thing that comes to our mind is probably breast cancer
.

HER2 is an important driver gene in breast cancer
.

However, HER2 has also emerged as an important molecular subtype in non-small cell lung cancer (NSCLC)
.

The proportion of HER2 mutation in lung cancer is relatively low, accounting for about 1% to 5% of non-small cell lung cancer, and the mutation mainly occurs in exon 20
.

At present, there is no precise drug targeting HER2 mutation in non-small cell lung cancer for clinical use, but the drug targeting this mutant gene is under continuous research and development
.

There are currently three classes of drugs, what are they? Today, we will introduce to you through an editorial review article [1]
.

Category 1: Tyrosine Kinase Inhibitor (TKI) Poziotinib is a pan-EGFR-targeted tyrosine kinase inhibitor (TKI) that inhibits mutations including HER2 exon 20 EGFR pathway
.

The results of clinical studies showed that the objective response rate (ORR) of poxitinib in patients with HER2 exon 20-mutated non-small cell lung cancer was 27%, and the median progression-free survival (PFS) was 5.
5 months [2,3] ]
.

According to this data, pozidetinib has some efficacy in this group, but the safety data seems to be problematic, because more than 70% of cases require dose reduction, and the incidence of rash and diarrhea related to treatment above grade 3 is also high [ 2,3]
.

Therefore, the drug seems to be more suitable for use in the later line at present
.

Of course, in order to reduce toxicity, researchers are currently trying other ways of administering pozytinib
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At the same time, other TKIs targeting HER2, such as Pyrotinib, are also under development
.

We will wait and see
.

Figure 1.
"Waterfall plot" (A) and PFS curve of pozidetinib in the treatment of HER2-mutated NSCLC [2] Category II: Monoclonal antibody combined with cytotoxic drug Mazieres Feasibility of trying dual HER2 monoclonal antibody combined with cytotoxic drug strategy in non-small cell lung cancer
.

Using Trastuzumab, Pertuzumab, and Docetaxel as treatment regimens, they observed an objective response rate of 29%, median progression-free survival (PFS) and sustained response time (DOR) were 6.
8 months and 11 months, respectively (Figure 1); unlike targeted therapy, patients receiving this combination regimen did not discontinue due to treatment-related adverse events (TRAEs), and this combination The most common TRAEs in the regimen were neutropenia and diarrhea [4]
.

Figure 2.
The efficacy "waterfall diagram" (A) and PFS curve (B) of IFCT-1703 R2D2 patients after treatment [4] Category 3: Antibody Conjugates (ADC) Many preclinical studies have confirmed that HER2 mutations can lead to body hypersensitivity, enhanced receptor ubiquitination and internalization, suggesting that the use of ADC drugs in HER2 mutations may be rational
.

TDM-1 (Trastuzumab-emtansine) and T-DXd (Trastuzumab deruxtecan) are two ADCs targeting HER2 mutations
.

A phase II clinical study showed that the objective response rate of 18 patients with HER2-mutated non-small cell lung cancer treated with TDM-1 was 44%, and the median progression-free survival was 5 months (Figure 3) [5]
.

Figure 3.
"Waterfall diagram" (A) and "swimming diagram" (B) of PFS for TDM-1 treatment [5] Compared with TDM-1, T-DXd antibody has higher drug loading rate and better cell membrane permeability, The indications for the treatment of breast cancer and gastric cancer have been approved by the US Food and Drug Administration (FDA)
.

The DESTINY-Lung01 study evaluated the efficacy and safety of the drug in HER2-mutant non-small cell lung cancer, and its objective response rate reached 55%, with a median progression-free survival of 8.
2 months, which is numerically superior to TDM-1 (of course this comparison is not scientific) (Figure 4) [6]
.

But in terms of safety, the incidence of interstitial pneumonia was 26%, of which 2 died [6]
.

After balancing efficacy and safety considerations, the FDA approved T-DXd for the treatment of HER2-mutant non-small cell lung cancer
.

Figure 4.
"Waterfall diagram" (A) and PFS curve (B) of T-DXd treatment [6] Summary and outlook: individualized treatment of HER2-mutated non-small cell lung cancer, progress and challenges coexist.
Mutant non-small cell lung cancer brings new treatment options (Figure 5) [1]
.

However, progress and challenges still coexist at present.
Whether TKIs, mAbs or ADCs, there are many unsolved problems waiting for us
.

In addition to the need for further confirmation of efficacy and safety, there are practical issues worth considering
.

For example, HER2 mutations are relatively rare, and large randomized controlled studies have limitations; when a treatment is assessed as disease progression, can other new therapies be used sequentially; the molecular mechanism of resistance to targeted therapy in HER2-mutated non-small cell lung cancer ; Treatment of special populations (such as brain metastases),
etc.

Figure 5.
Schematic diagram of three types of treatments for HER2-mutant NSCLC[1] The dawn has come, and we believe that more and more research evidence will answer these questions one by one, and provide a basis for the personalized treatment of HER2-mutant non-small cell lung cancer.
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.

References: (swipe up and down to view) 1.
Alissa J Cooper, et al.
Human Epidermal Growth Factor Receptor 2-Mutant Non-Small-Cell Lung Cancer: Continued Progress But Challenges Remain.
Journal of Clinical Oncology.
2022; 40(7 ): 693-697.
2.
Yasir Y Elamin, et al.
Poziotinib for Patients With HER2 Exon 20 Mutant Non-Small-Cell Lung Cancer: Results From a Phase II Trial.
Journal of Clinical Oncology.
2022; 40(7): 702- 709.
3.
Xiuning Le, et al.
Poziotinib in Non-Small-Cell Lung Cancer Harboring HER2 Exon 20 Insertion Mutations After Prior Therapies: ZENITH20-2 Trial.
Journal of Clinical Oncology.
2022; 40(7): 710-718.
4.
Julien Mazieres , et al.
Combination of Trastuzumab, Pertuzumab, and Docetaxel in Patients With Advanced Non-Small-Cell Lung Cancer Harboring HER2 Mutations: Results From the IFCT-1703 R2D2 Trial.
Journal of Clinical Oncology.
2022; 40(7): 719- 728.
5.
Bob T Li,et al.
Ado-Trastuzumab Emtansine for Patients With HER2-Mutant Lung Cancers: Results From a Phase II Basket Trial.
Journal of Clinical Oncology.
2018; 36(24): 2532-2537.
6.
Bob T Li, et al.
Trastuzumab Deruxtecan in HER2-Mutant Non-Small-Cell Lung Cancer.
The New England Journal of Medicine.
2022; 386(3): 241-251.
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