Pyrotinib combined with thalidomide in advanced non-small-cell lung cancer patients harboring HER2 exon 20 insertions (PRIDE): protocol of an open-label, single-arm phase II trial

Abstract

Background Standard therapy for human epidermal growth factor receptor 2 (HER2)-mutant non-small-cell lung cancer (NSCLC) is lacking. The clinical benefits with pan-HER inhibitors (afatinib, neratinib, and dacomitinib), anti-HER2 antibody drug conjugate (ADC) trastuzumab emtansine, and an emerging irreversible tyrosine kinase inhibitor (TKI) poziotinib were modest. Another new ADC trastuzumab deruxtecan showed encouraging outcomes, but only phase I study was completed. Pyrotinib, another emerging irreversible epidermal growth factor receptor (EGFR)/HER2 dual TKI, has been approved in HER2-positive breast cancer in 2018 in China. It has shown promising antitumor activity against HER2-mutant NSCLC in phase II trials, but pyrotinib-related diarrhea remains an issue. The antiangiogenic and immunomodulatory drug thalidomide is a cereblon-based molecular glue that can induce the degradation of the IKAROS family transcription factors IKZF1 and IKZF3. The use of thalidomide can also decrease gastrointestinal toxicity induced by anti-cancer therapy. Methods This is an open-label, single-arm phase II trial. A total of 39 advanced NSCLC patients with HER2 exon 20 insertions and ≤ 2 lines of prior chemotherapy will be recruited, including treatment-naïve patients who refuse chemotherapy. Patients are allowed to have prior therapy with immune checkpoint inhibitors and/or antiangiogenic agents. Those who have prior HER2-targeting therapy or other gene alterations with available targeted drugs are excluded. Eligible patients will receive oral pyrotinib 400 mg once daily and oral thalidomide 200 mg once daily until disease progression or intolerable toxicity. The primary endpoint is objective response rate. Discussion The addition of thalidomide to pyrotinib is expected to increase the clinical benefit in advanced NSCLC patients with HER2 exon 20 insertions, and reduce the incidence of pyrotinib-related diarrhea. We believe thalidomide is the stone that can hit two birds. Trial registration ClinicalTrials.gov Identifier: NCT04382300. Registered on May 11, 2020.

Molecular and clinicopathological characteristics of ERBB2 gene fusions in 32,131 Chinese patients with solid tumors

“…In addition to antibody drugs, several small-molecule HER2 kinase inhibitors, including pyrotinib and lapatinib, are available approved agents for patients with HER2-positive breast cancer. Besides, pyrotinib has demonstrated a good potential to treat advanced NSCLC with ERBB2 mutations, especially the ERBB2 exon 20 insertions, in the phase II studies ( 40 , 41 ). In view of their drug mechanisms which bind to the HER2 kinase domain, pyrotinib or lapatinib can be a potential option for cancer patients with ERBB2 fusions, especially those X-ERBB2 fusions, which needs to be prospectively explored.…”

Hormone receptor-positive, HER2-negative, metastatic breast cancer responded well to abemaciclib and exemestane after palbociclib and fulvestrant failure: A case report and literature review

“…role in cancer control. One recent study found that adding thalidomide to pyrotinib increased clinical benefit for advanced non-small-cell lung cancer (NSCLC) patients with HER2 exon 20 insertions, with reductions in the incidence of pyrotinib-related diarrhea (15). In a breast cancer murine model, Yang Jin et al found that thalidomide inhibited breast tumor growth through inhibition of angiogenesis by reducing tumor-associated macrophage accumulation and infiltration and decreasing angiogenesis-related cytokine production (14).…”

“…There are many studies that have shown thalidomide to be immunomodulatory, to have anti-angiogenic activities that may suppress tumor growth ( 12 – 14 ), and to play an important role in cancer control. One recent study found that adding thalidomide to pyrotinib increased clinical benefit for advanced non-small-cell lung cancer (NSCLC) patients with HER2 exon 20 insertions, with reductions in the incidence of pyrotinib-related diarrhea ( 15 ). In a breast cancer murine model, Yang Jin et al.…”

Mechanistic Studies and a Retrospective Cohort Study: The Interaction between PPAR Agonists and Immunomodulatory Agents in Multiple Myeloma

“…Cereblon (CRBN) is a substrate adaptor in the CRL4 CRBN E3 ubiquitin ligase complex, that alters the substrate specificity of the complex following binding with IMiDs [ 17 , 18 , 19 ]. The binding of IMiDs to CRBN results in the ubiquitination and degradation of several factors, including the IKZF1 and IKZF3 transcription factors [ 20 , 21 ]. The degradation of these factors inhibits the survival and progression of MM cells [ 22 , 23 , 24 ].…”