Efficacy and safety of pan-ErbB inhibitor pyrotinib combined with antiangiogenic agent apatinib for HER2-mutant or amplified metastatic NSCLC: A phase II clinical study.

9035 Background: Tumor angiogenesis could be induced by activation of HER2 receptor, and currently, there is lack of clinical evidence of anti-HER2 tyrosine kinase inhibitors (TKIs) combined with antiangiogenic therapy for HER2-mutant or amplified non-small cell lung cancer (NSCLC). We conducted a study to explore the efficacy and safety of a pan-ErbB inhibitor pyrotinib combined with apatinib for metastatic NSCLC patients harboring HER2 amplification or activating mutations. Methods: This was a single-center, single-arm phase II study with Simon’s optimal two-stage design. Metastatic NSCLC patients with ECOG scores of 0-1 and harboring primary HER2 amplification, exon 20 insertion or activating missense mutations who had failed to prior chemotherapies or anti-HER2 TKIs were eligible to be enrolled. All patients received oral pyrotinib (400mg once daily) combined with apatinib (250mg once daily) therapy. The primary endpoint was objective response rate (ORR), and second endpoints included progression-free survival (PFS), duration of response (DoR), disease control rate (DCR), overall survival (OS) and safety. Results: Between March 5, 2019, and December 1, 2020, 33 metastatic NSCLC patients with HER2 alterations were enrolled, including exon 20 insertions (A775_G776insYVMA, 20/33; P780_Y781insGSP, 6/33; other variants, 2/33), missense mutations (3/33), and primary HER2 amplification (2/33). Seventeen patients (51.5%) were pretreated with first-line platinum-based chemotherapies or anti-HER2 TKIs, and the remaining had received at least 2 lines of prior therapies (range, 2-6). At the last follow-up time January 23, 2021, the overall ORR and DCR were 45.5% (15/33) and 93.9% (31/33), respectively. The median PFS was 6.8 (95%CI: 5.4-8.2) months. The median DoR and OS were 5.3 (95%CI: 0-11.8) and 12.9 (95%CI: 8.6-17.2) months, respectively. The mPFS was significantly longer in patients who received second-line pyrotinib combined with apatinib therapy than those in third- or above-line settings (9.8 vs. 5.3 months, P = 0.018, HR = 0.281 [95%CI: 0.098-0.807]). Although pyrotinib combined with apatinib therapy showed similar ORRs in patients with presence (46.2%, 6/13) or absence (45.0%, 9/20) of brain metastases, and those in second-line (47.1%, 8/17) or above-line settings (43.8%, 7/16). Common treatment-related adverse events (AEs) were grade 1-2, mainly including diarrhea (90.9%), hypertension (72.7%), asthenia (63.6%), anorexia (54.5%) and nausea (51.5%). Grade 3 AEs were diarrhea (3.0%) and hypertension (9.1%). No grade 4 or 5 AE or treatment-related deaths were reported. Conclusions: Pyrotinib combined with apatinib showed potent anti-tumor activity and acceptable safety profile in metastatic NSCLC with HER2 amplification or activating mutations. Clinical trial information: ChiCTR1900021684.