HER2 (also known as ERBB2) is a transmembrane glycoprotein receptor with intracellular tyrosine kinase activity and is a member of the ERBB family. HER2 mutations include HER2 mutations, HER2 amplification, and HER2 overexpression. In non-small cell lung cancer (NSCLC), HER2 is also a well-defined oncogenic driver. Human epidermal growth factor receptor 2 (HER2) mutations occur in 2% of lung cancers and lead to enhanced EGFR signaling, promoting sustained differentiation, proliferation, and metastasis of tumor cells.
HER2-mutated advanced NSCLC is a class of NSCLC with a poor prognosis. HER2-mutant lung cancer remains an "orphan" for any particular targeted therapy. There are still many unsolved mysteries left for us clinicians to explore and solve. Today, I would like to introduce to you several mainstream strategies for HER2-mutant NSCLC.
1. Pyrotinib
A multicenter, open-label, single-arm phase II study investigated the efficacy of pyrotinib in patients with HER2-mutated advanced lung adenocarcinoma who have progressed after platinum-based chemotherapy.
Methods: Continuous oral pyrotinib at a dose of 400 mg per day for 21 days within 30 minutes after breakfast until disease progression, unacceptable toxicity, or withdrawal of consent.
Results: Between October 20, 2016 and December 10, 2018, 86 patients were screened, of whom 60 patients received pyrotinib monotherapy. At baseline, 58 (96.7%) patients were in stage IV and 25 (41.7%) had received at least 2 lines of chemotherapy. As of June 20, 2019, the objective response rate (ORR) assessed by the Independent Review Committee was 30.0% (95% CI, 18.8%-43.2%) as of the data cut-off. All subgroups of patients with different HER2 mutation types demonstrated good ORRs. The ORR was similar for patients with brain metastases and those without brain metastases (25.0% vs. 31.3%). Median progression-free survival (PFS) was 6.9 months (95% CI, 5.5 to 8.3 months). Median overall survival (OS) was 14.4 months (95% CI, 12.3 to 21.3 months). Grade 3 or 4 treatment-related adverse events occurred in 28.3% of patients, with diarrhea being the most common (20.0%; All are level 3). There were no treatment-related deaths.
Conclusions: Pyrotinib shows good anti-tumor activity and safety in patients with HER2-mutant NSCLC.
2. Afatinib
Afatinib mainly acts on the covalent binding region of EGFR (ErbB1), HER2 (ErbB2) and HER4 (ErbB4) kinases, and can irreversibly inhibit tyrosine kinase autophosphorylation, resulting in down-regulation of ErbB signaling and inhibition of tumor growth.
A real-world study published in The Oncologist explored the efficacy of afatinib in the treatment of HER2-mutant lung adenocarcinoma.
Results: Thirty-two patients with HER2-mutated lung cancer after failure of multiple lines of therapy were included in this study. The ORR and disease control rate (DCR) were 15.6% (95% CI, 5.9%-33.6%) and 68.8% (95% CI, 49.9%-83.3%) in the afatinib arm, respectively. After treatment with afatinib, 28 patients (87.5%) experienced disease progression. Median PFS for all patients and responders was 3.2 months (95% CI, 2.0-4.5 months) and 7.6 months (95% CI, 3.8-11.5 months), respectively. The longest PFS (12.0 months) was observed in 1 patient with the G776DelinSVC mutation. Overall survival data are immature. Different HER2 missense mutations also exhibited different susceptibility to afatinib; In particular, patients with G778_P780DUP and G776DelinSVC (two non-YVMA exon 20 insertions) had a higher sensitivity to afatinib than other variants. Advantage. The findings also suggest heterogeneity in HER2-mutant lung cancer. In future diagnostic and therapeutic paradigms, screening patients based on HER2 variants and co-mutation patterns may help identify effective anti-HER2 therapies.
Afatinib Bengal Bicon
3. Pertuzumab + trastuzumab + docetaxel triple regimen
This triple regimen was originally derived from a therapeutic strategy for HER2-mutated breast cancer. This strategy is primarily derived from a multicenter, non-randomized phase II IFCT 1703-R2D2 study[3].
Methods: Patients received loading doses of pertuzumab 840 mg and 420 mg, respectively; The loading dose of trastuzumab is 8 mg/kg, followed by 6 mg/kg; and docetaxel at 75 mg/m2 every 3 weeks. The primary endpoint is ORR. Other endpoints included duration of response, PFS, and safety.
Results: Forty-five patients were enrolled for treatment. The median age was 64.5 years (range 31~84 years), 35% of the patients were smokers, 72% of the patients were females, 15% of the patients had an ECOG score of 2, and 30% of the patients had brain metastases. The ORR was 29%, and 58% of patients were in stable disease (SD). The median PFS was 6.8 months (95%CI, 4.0~8.5). Among patients with confirmed response, the median duration of response was 11 months (95% CI, 2.9~14.9). Grade 3/4 treatment-related adverse events were observed in 64% of patients, and no patients discontinued treatment due to adverse events. The most common grade 3 treatment-related adverse events were neutropenia (33%), diarrhoea (13%), and anemia (9%). The study suggests that trastuzumab + pertuzumab + docetaxel triple therapy is feasible and effective in the treatment of HER2-mutated advanced NSCLC.
4、T-DM1
T-DM1 generic name: trastuzumab for injection; T-DM1 is a combination of trastuzumab, a classical anti-HER2-targeting drug, and the chemotherapeutic drug maytansol, which inhibits microtubule aggregation through thioether linkers. It has the characteristics of a "panacea" that targets tumor cells and can directly deliver potent chemotherapy drugs to HER2-positive cancer cells. The antibody part recognizes a special protein on the surface of cancer cells, so that powerful chemotherapy drugs can be delivered to the tumor site with precision and precision. In this way, it can not only give full play to the effect of targeted drugs, but also exert the killing effect of chemotherapy, while limiting the immunity of healthy tissues. harm.
The main study is a Phase II clinical study to explore the efficacy of T-DM1 in the treatment of HER2-overexpressing metastatic NSCLC.
Methods: Eligible patients were treated with HER2-overexpressing NSCLC. Patients are divided into cohorts according to HER2IHC (2, 3). All patients received T-DM 13.6 mg/kg intravenously every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint is investigator-determined ORR.
Results: Forty-nine patients were treated with T-DM1 (29 IHC2 and 20 IHC3). No reactions were observed in the IHC2 cohort. A partial response (ORR20%; 95%CI5.7-43.7%）。 The clinical benefit rates for the IHC2 and 3 cohorts were 7% and 30%, respectively. The response time for responders was 2.9, 7.3, 8.3, and 10.8 months, respectively. Three of the four responders developed HER2 gene amplification.
Studies have shown that T-DM1 shows significant activity in patients with HER2-overexpressing advanced NSCLC (IHC3), but further exploration is still needed to refine the target population of T-DM1.
5. Star drug: DS-8201
DS-8201 (trastuzumab/deruxtecan), T-DXd is a second-generation ADC drug consisting of an anti-HER2IgG1 monoclonal antibody via an adapter and a topoisomerase I inhibitor Dxd (10 times stronger than irinotecan).
The main study is DESTINY-Lung01. DESTINY-Lung01 is an open-label, multicenter, multi-cohort Phase II clinical study in two cohorts of patients with unresectable and/or metastatic non-squamous NSCLC: 1. HER2 overexpression (immunohistochemistry 2 or 3) cohorts, 2. HER2-mutated NSCLC cohorts, and the efficacy of DS-8201 was primarily evaluated in two cohorts. The primary endpoint is ORR as assessed by ICR (Independent Central Review Committee).
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HER2 overexpression (immunohistochemistry 2 or 3) cohorts
Methods: Patients with HER2 overexpression metastatic NSCLC were treated with 6.4 mg/kg T-DXd every 3 weeks. The primary endpoint of ICR assessment is ORR (CRPR). Other endpoints included DCR (CRPRSD), duration of response (DOR), PFS, and safety.
Results: As of May 31, 2020, 49 patients have undergone T-DXd. Among them, HER2IHC2 accounted for 79.6% and HER2IHC3 accounted for 20.4%. 91.8% of the patients had received prior platinum-based chemotherapy and 73.5% had received prior anti-PD-1/PD-L1 therapy.
ICR confirmed an ORR of 24.5% (95% CI, 13.3%-38.9%), of which 1 patient achieved CR and 11 patients achieved PR; The ORR of IHC2 patients was 25.6% (95% CI, 13.0%-42.1%); Patients with IHC3 had an ORR of 20.0% (95% CI, 2.5%-55.6%) and a median PFS of 5.4 months (95% CI: 2.8-7.0). The median DOR was 6.0 months (95% CI, 3.2-NE months); The DCR was 69.4% (95% CI, 54.6%-81.8%).
2.HER2突变NSCLC队列
Methods: Patients with HER2 mutant NSCLC metastases received T-DXd (6.4 mg/kg body weight). The primary endpoint was ORR as assessed by independent central review. Secondary endpoints included duration of response, PFS, OS, and safety.
Results: A total of 91 patients were enrolled. The median follow-up was 13.1 months (0.7-29.1). The median duration of response was 9.3 months (95% CI, 5.7 to 14.7). Median PFS was 8.2 months (95% CI, 6.0-11.9) and median OS was 17.8 months (95% CI, 13.8-22.1). The safety profile is generally consistent with previous studies; Forty-six percent of patients experienced treatment-related adverse events of grade 3 or higher, with neutropenia being the most common event (19 percent). Treatment-related interstitial lung disease occurred in 26% of patients, with 2 patients dying. Studies have shown that DS-8201 shows durable anticancer activity in previously treated patients with HER2-mutant NSCLC.
The search for HER2-mutant non-small cell lung cancer has not stopped. Although the current treatment strategy is like a spark, the emergence of innovative drugs has also allowed us to see the trend of the prairie fire.
Tips: The medical content involved in this article is a general application suggestion, which is for learning and reference only, and the final opinion is subject to the diagnosis of the clinician.