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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.

Peer Review reports

Background

Mutations in human epidermal growth factor receptor 2 (HER2, neu or ERBB2) are found in approximately 2–6.7% of patients with non-small-cell lung cancer (NSCLC) [1,2,3], and the median overall survival (OS) in this subpopulation is around 22.9 months from the diagnosis of metastatic disease [1]. This mutation is prone to be found in non-smokers and females, and the histological type is more likely to be adenocarcinoma or adenosquamous carcinoma [4,5,6,7]. During the past few years, various HER2-targeting therapeutic strategies for HER2-mutant NSCLC were developed, including pan-HER inhibitors (afatinib, neratinib, and dacomitinib) [8,9,10], anti-HER2 antibody drug conjugates (ADCs; such as trastuzumab emtansine [T-DM1]) [11], and emerging irreversible tyrosine kinase inhibitors (TKIs; such as poziotinib) [12]. However, the clinical benefits with these drugs were modest, with the objective response rate (ORR) of 4–44% and median progression-free survival (PFS) of 3.0–5.6 months [8,9,10,11,12]. The new ADC trastuzumab deruxtecan (DS-8201a) brought encouraging clinical benefits for HER2-mutant NSCLC. The ORR and median PFS were 73% (8/11) and 11.3 months with trastuzumab deruxtecan in patients with HER2-mutant NSCLC, respectively [13]. However, only exploratory phase I results of this novel potent drug were reported at present. Until now, chemotherapy is still the stand of care for this population, and novel treatment strategy is urgently needed.

Pyrotinib is an oral, irreversible epidermal growth factor receptor (EGFR)/HER2 dual TKI. The combination of pyrotinib with capecitabine has been approved for the treatment of patients with HER2-positive, relapsed or metastatic breast cancer who were previously treated with taxanes, anthracyclines, and/or trastuzumab in China [14]. In a HER2 exon 20 insertion patient-derived xenografts model, a more profound tumor regression was observed with pyrotinib than with afatinib and T-DM1 [15]. Two phase II trials have demonstrated the promising antitumor activity and acceptable safety profile of pyrotinib monotherapy in patients with previously treated, HER2-mutant advanced NSCLC, with the ORR of 53% (8/15) and 30% (18/60), and median PFS of 6.4 and 6.9 months, respectively [15, 16]. A multicenter, randomized phase III trial (NCT04447118) has been started to compare the efficacy and safety of pyrotinib versus docetaxel in patients with advanced non-squamous NSCLC harboring HER2 exon 20 mutations who failed platinum-based chemotherapy. However, pyrotinib-related diarrhea remains an issue, with the incidence of 27% (4/15) and 92% (55/60) in previous phase II trials [15, 16]. Thus, we wanted to explore a combination regimen to further enhance the antitumor activity and improve the safety and tolerability of pyrotinib in advanced NSCLC patients with HER2 exon 20 insertions.

Thalidomide, a derivative of glutamic acid, is an antiangiogenic and immunomodulatory drug. It has been extensively used in patients with multiple myeloma for decades [17, 18]. These years, thalidomide has been proved to be one of the molecular glues that can induce the protein degradation of undruggable targets, which can compromise the limitation of inhibitors [19]. By binding cereblon (CRBN), thalidomide can activate the E3 ubiquitin ligase CRL4CRBN-mediated ubiquitination and degradation of the IKAROS family transcription factors IKZF1 and IKZF3 [19], which play key roles in the tumorigenesis and progression of hematologic malignancies [20]. For solid cancers, the clinical activity of thalidomide monotherapy is limited [21], but recent in vitro studies demonstrated the synergistic effects of thalidomide in combination with TKIs on NSCLC [22, 23]. A pilot study of thalidomide plus erlotinib in 52 advanced NSCLC patients with acquired resistance to erlotinib indicated the reversion effect of thalidomide on TKI-acquired resistance [24]. In addition to the antiangiogenic and immunomodulatory actions, the characteristic of thalidomide as a molecular glue may contribute to the synergistic effect in solid cancers. On the other hand, a striking absence of diarrhea was observed when thalidomide was added to chemotherapy [25, 26]. Thus, we hypothesized that the addition of thalidomide to pyrotinib might increase the clinical benefit and reduce the incidence of pyrotinib-related diarrhea.

Therefore, this PRIDE study is conducted to investigate the efficacy and safety of pyrotinib combined with thalidomide in advanced NSCLC patients with HER2 exon 20 insertions.

Methods/design

Study design

This is a single-center, open-label, single-arm phase II trial (ClinicalTrials.gov Identifier: NCT04382300) in advanced NSCLC patients with HER2 exon 20 insertions (Fig. 1). The study is being conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. The protocol and its amendments have been approved by the ethics committee of Shanghai Chest Hospital (No. LS2003). The recruitment was started on May 25, 2020, and the first patient was recruited on June 24, 2020. The enrolment is estimated to be completed in December 2021 for the first stage and in December 2022 for the second stage.

Eligibility criteria

The patient inclusion and exclusion criteria are detailed in Table 1.

Table 1 Eligibility criteria
Fig. 1
figure1

Study design

HER2 mutation confirmation

HER2 exon 20 insertions will be confirmed by next generation sequencing, amplification refractory mutation system-polymerase chain reaction, or droplet digital polymerase chain reaction. Tumor tissues obtained from biopsy or circulating tumor DNA from blood samples can be used for HER2 testing. If blood samples are used, the mutation abundance should be ≥10%. The gene mutation reports from other testing organizations are allowed.

Intervention

Eligible patients will receive oral pyrotinib 400 mg once daily and oral thalidomide 200 mg once daily until disease progression, intolerable toxicity, withdrawal of consent, or other reasons judged by the investigator. Dose adjustment, interruption, or discontinuation of study drug according to the adverse events (AEs) is detailed in Table 2.

Table 2 Dose adjustment criteria

Endpoints

The primary endpoint is ORR. The secondary endpoints are PFS, OS, disease control rate, safety, and patient-reported outcomes (European Organization for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire-Core 30 [QLQ-C30] and Quality of Life Questionnaire-Lung Cancer Module 13 [QLQ-LC13]) [29, 30].

Imaging examinations using computed tomography or magnetic resonance imaging will be conducted at baseline, 3 weeks, and every 6 weeks thereafter. Tumor response will be assessed according to the Response Evaluation Criteria In Solid Tumors, version 1.1 [27]. AEs during the treatment period and within 28 days after the last dose will be recorded and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Survival status will be followed by telephone every 3 months until death, lost to follow-up, or the termination of the study. Subsequent anti-cancer treatment after disease progression or discontinuation of the study treatment will be recorded.

Statistical analysis

Simon’s two-stage minmax design was selected for sample size calculation. The combination therapy with pyrotinib and thalidomide will be ineffective or uninteresting if the ORR is lower than 30% and this regimen will be worthy of further study if the ORR is ≥50%. A total sample of at least 39 patients is expected to provide 80% power for the analysis at the significance level of 0.05, including 19 patients in the first stage and 20 patients in the second stage of the trial. If six or more patients respond at the completion of the first stage, the second stage can be conducted. Otherwise, the study will be terminated. If at least 16 of 39 patients show response, this combination therapy is effective and warrants further study.

Following intent-to-treat principle, the efficacy analyses will be performed in the full analysis set, defined as all patients who received at least one dose of study drug with at least one efficacy evaluation. Safety analyses will be performed in the safety set, defined as all patients who received at least one dose of study drug with at least one safety record. Descriptive statistics will be conducted on baseline characteristics, tumor response, patient-reported outcomes, and AEs. Survival curves will be plotted using Kaplan-Meier method. No data imputation will be performed for the missing data.

Discussion

This study will provide evidence on the efficacy and safety of pyrotinib plus thalidomide in advanced NSCLC patients with HER2 exon 20 insertions, which may be used as a candidate standard therapy.

A previous in vitro study demonstrated the superior effect of pyrotinib on tumor regression compared with afatinib and T-DM1 [15], and indirect comparisons showed a relatively higher median PFS with pyrotinib (6.4–6.9 months) than with other pan-HER inhibitors and ADC T-DM1 (3.0–5.6 months) [8,9,10,11,12]. Although a multicenter, randomized phase III trial (NCT04447118) has been started to verify the efficacy and safety of pyrotinib versus docetaxel in patients with previously treated, advanced non-squamous NSCLC harboring HER2 exon 20 mutations, we considered that a combination regimen is worth of exploration to further enhance the antitumor activity and improve the safety and tolerability of pyrotinib. We believe thalidomide is the precious stone that can hit two birds.

Patient-reported outcomes are effective tools to directly measure the experiences of patients with cancer, which are more and more important in oncology studies [31]. The incidence of pyrotinib-related diarrhea is terrible, with 92% (55/60) of any grade diarrhea and 20% (12/60) of grade 3–4 diarrhea in a phase II trial [16]. The frequent occurrence of diarrhea negatively impacts patient quality of life and tolerability. Dose adjustment and interruption due to diarrhea may reduce the efficacy of pyrotinib. Constipation caused by thalidomide can counteract the diarrhea from anti-cancer therapy, which is supported by previous clinical trials [25, 26]. In addition, thalidomide can decrease nausea and vomiting induced by chemotherapy [32], which are also the common AEs of pyrotinib [14,15,16]. We believed that the use of thalidomide with synergistic antitumor effect and attenuation of gastrointestinal toxicity is a better option compared with prophylactic antidiarrheal drugs (such as loperamide) for patients treated with pyrotinib. The use of this combination therapy may improve the tolerability and compliance of patients and do not increase too much financial burden compared with pyrotinib monotherapy, which can be reflected by the results of EORTC QLQ-C30 and QLQ-LC13.

Considering the cardiac toxicity and the risk of thrombosis/embolism events in the use of thalidomide [33, 34], the adequate cardiac function was set as an inclusion criteria and history of cardiac diseases or thrombus were set as exclusion criteria to reduce the risk of patients. However, we still need to be alert to the potential unexpected safety signals when this combination therapy is administered.

In terms of clinical practice, some patients may refuse the chemotherapy due to the tolerability concerns. These patients will be enrolled in the present study, and it should be noted that some patients with previously untreated, advanced NSCLC harboring HER2 exon 20 insertions will receive pyrotinib plus thalidomide. Thus, this study will provide preliminary evidence of this combination therapy in the first-line setting.

We wish that the present study will find a potent chemo-free treatment approach and bring new light of hope for advanced NSCLC patients with HER2 exon 20 insertions.

Availability of data and materials

Not applicable.

Abbreviations

ADC:

Antibody drug conjugate

AE:

Adverse event

CRBN:

Cereblon

EGFR:

Epidermal growth factor receptor

EORTC:

European Organization for Research and Treatment of Cancer

HER2:

Human epidermal growth factor receptor 2

NSCLC:

Non-small-cell lung cancer

ORR:

Objective response rate

OS:

Overall survival

PFS:

Progression-free survival

QLQ-C30:

Quality of Life Questionnaire-Core 30

QLQ-LC13:

Quality of Life Questionnaire-Lung Cancer Module 13

T-DM1:

Trastuzumab emtansine

TKI:

Tyrosine kinase inhibitor

References

  1. 1.

    Mazières J, Peters S, Lepage B, Cortot AB, Barlesi F, Beau-Faller M, et al. Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives. J Clin Oncol. 2013;31(16):1997–2003. https://doi.org/10.1200/JCO.2012.45.6095.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Pillai RN, Behera M, Berry LD, Rossi MR, Kris MG, Johnson BE, et al. HER2 mutations in lung adenocarcinomas: a report from the lung Cancer mutation consortium. Cancer. 2017;123(21):4099–105. https://doi.org/10.1002/cncr.30869.

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Kim EK, Kim KA, Lee CY, Shim HS. The frequency and clinical impact of HER2 alterations in lung adenocarcinoma. PLoS One. 2017;12(2):e0171280. https://doi.org/10.1371/journal.pone.0171280.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Shigematsu H, Takahashi T, Nomura M, Majmudar K, Suzuki M, Lee H, et al. Somatic mutations of the HER2 kinase domain in lung adenocarcinomas. Cancer Res. 2005;65(5):1642–6. https://doi.org/10.1158/0008-5472.CAN-04-4235.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Tomizawa K, Suda K, Onozato R, Kosaka T, Endoh H, Sekido Y, et al. Prognostic and predictive implications of HER2/ERBB2/neu gene mutations in lung cancers. Lung Cancer. 2011;74(1):139–44. https://doi.org/10.1016/j.lungcan.2011.01.014.

    Article  PubMed  Google Scholar 

  6. 6.

    Sholl LM, Aisner DL, Varella-Garcia M, Berry LD, Dias-Santagata D, Wistuba II, et al. Multi-institutional oncogenic driver mutation analysis in lung adenocarcinoma: the lung Cancer mutation consortium experience. J Thorac Oncol. 2015;10(5):768–77. https://doi.org/10.1097/JTO.0000000000000516.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Bu S, Wang R, Pan Y, Yu S, Shen X, Li Y, et al. Clinicopathologic characteristics of patients with HER2 insertions in non-small cell lung Cancer. Ann Surg Oncol. 2017;24(1):291–7. https://doi.org/10.1245/s10434-015-5044-8.

    Article  PubMed  Google Scholar 

  8. 8.

    Dziadziuszko R, Smit EF, Dafni U, Wolf J, Wasąg B, Biernat W, et al. Afatinib in NSCLC with HER2 mutations: results of the prospective, open-label phase II NICHE trial of European thoracic oncology platform (ETOP). J Thorac Oncol. 2019;14(6):1086–94. https://doi.org/10.1016/j.jtho.2019.02.017.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Hyman DM, Piha-Paul SA, Won H, Rodon J, Saura C, Shapiro GI, et al. HER kinase inhibition in patients with HER2- and HER3-mutant cancers. Nature. 2018;554(7691):189–94. https://doi.org/10.1038/nature25475.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Kris MG, Camidge DR, Giaccone G, Hida T, Li BT, O'Connell J, et al. Targeting HER2 aberrations as actionable drivers in lung cancers: phase II trial of the pan-HER tyrosine kinase inhibitor dacomitinib in patients with HER2-mutant or amplified tumors. Ann Oncol. 2015;26(7):1421–7. https://doi.org/10.1093/annonc/mdv186.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Li BT, Shen R, Buonocore D, Olah ZT, Ni A, Ginsberg MS, et al. Ado-Trastuzumab Emtansine for patients with HER2-mutant lung cancers: results from a phase II basket trial. J Clin Oncol. 2018;36(24):2532–7. https://doi.org/10.1200/JCO.2018.77.9777.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Robichaux JP, Elamin YY, Vijayan RSK, Nilsson MB, Hu L, He J, et al. Pan-Cancer Landscape and Analysis of ERBB2 Mutations Identifies Poziotinib as a Clinically Active Inhibitor and Enhancer of T-DM1 Activity. Cancer Cell. 2019;36(4):457.e7. https://doi.org/10.1016/j.ccell.2019.09.001.

    CAS  Article  Google Scholar 

  13. 13.

    Tsurutani J, Iwata H, Krop I, Jänne PA, Doi T, Takahashi S, et al. Targeting HER2 with Trastuzumab Deruxtecan: a dose-expansion, phase I study in multiple advanced solid tumors. Cancer Discov. 2020;10(5):688–701. https://doi.org/10.1158/2159-8290.CD-19-1014.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Ma F, Ouyang Q, Li W, Jiang Z, Tong Z, Liu Y, et al. Pyrotinib or Lapatinib combined with Capecitabine in HER2-positive metastatic breast Cancer with prior Taxanes, Anthracyclines, and/or Trastuzumab: a randomized, Phase II Study. J Clin Oncol. 2019;37(29):2610–9. https://doi.org/10.1200/JCO.19.00108.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Wang Y, Jiang T, Qin Z, Jiang J, Wang Q, Yang S, et al. HER2 exon 20 insertions in non-small-cell lung cancer are sensitive to the irreversible pan-HER receptor tyrosine kinase inhibitor pyrotinib. Ann Oncol. 2019;30(3):447–55. https://doi.org/10.1093/annonc/mdy542.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Zhou C, Li X, Wang Q, Gao G, Zhang Y, Chen J, et al. Pyrotinib in HER2-mutant advanced lung adenocarcinoma after platinum-based chemotherapy: a multicenter, open-label, single-arm, Phase II Study. J Clin Oncol. 2020;38(24):2753–61. https://doi.org/10.1200/JCO.20.00297.

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999;341(21):1565–71. https://doi.org/10.1056/NEJM199911183412102.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol. 2003;21(1):16–9. https://doi.org/10.1200/JCO.2003.03.139.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Fischer ES, Böhm K, Lydeard JR, Yang H, Stadler MB, Cavadini S, et al. Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide. Nature. 2014;512(7512):49–53. https://doi.org/10.1038/nature13527.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Rebollo A, Schmitt C. Ikaros, Aiolos and Helios: transcription regulators and lymphoid malignancies. Immunol Cell Biol. 2003;81(3):171–5. https://doi.org/10.1046/j.1440-1711.2003.01159.x.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Pan B, Lentzsch S. The application and biology of immunomodulatory drugs (IMiDs) in cancer. Pharmacol Ther. 2012;136(1):56–68. https://doi.org/10.1016/j.pharmthera.2012.07.004.

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Sun X, Xu Y, Wang Y, Chen Q, Liu L, Bao Y. Synergistic inhibition of thalidomide and Icotinib on human non-small cell lung carcinomas through ERK and AKT signaling. Med Sci Monit. 2018;24:3193–203. https://doi.org/10.12659/MSM.909977.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Xia X, Liu Y, Liao Y, Guo Z, Huang C, Zhang F, et al. Synergistic effects of gefitinib and thalidomide treatment on EGFR-TKI-sensitive and -resistant NSCLC. Eur J Pharmacol. 2019;856:172409. https://doi.org/10.1016/j.ejphar.2019.172409.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Wang G-H, Wu P-F, Zhang L-H, Fang P, Chen Y, Zuo G, et al. Use of erlotinib and thalidomide in advanced NSCLC patients with acquired resistance to erlotinib: a pilot study. Pathol Res Pract. 2018;214(2):263–7. https://doi.org/10.1016/j.prp.2017.10.016.

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Govindarajan R, Heaton KM, Broadwater R, Zeitlin A, Lang NP, Hauer-Jensen M. Effect of thalidomide on gastrointestinal toxic effects of irinotecan. Lancet. 2000;356(9229):566–7. https://doi.org/10.1016/S0140-6736(00)02586-1.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Miller AA, Case D, Atkins JN, Giguere JK, Bearden JD. Phase II study of carboplatin, irinotecan, and thalidomide in patients with advanced non-small cell lung cancer. J Thorac Oncol. 2006;1(8):832–6. https://doi.org/10.1097/01243894-200610000-00012.

    Article  PubMed  Google Scholar 

  27. 27.

    Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47. https://doi.org/10.1016/j.ejca.2008.10.026.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Goldstraw P. Staging manual in thoracic oncology. 1st ed. Orange Park: Editorial Rx Press; 2009.

    Google Scholar 

  29. 29.

    Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85(5):365–76. https://doi.org/10.1093/jnci/85.5.365.

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Bergman B, Aaronson NK, Ahmedzai S, Kaasa S, Sullivan M. The EORTC QLQ-LC13: a modular supplement to the EORTC Core quality of life questionnaire (QLQ-C30) for use in lung cancer clinical trials. EORTC study group on quality of life. Eur J Cancer. 1994;30A(5):635–42. https://doi.org/10.1016/0959-8049(94)90535-5.

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    LeBlanc TW, Abernethy AP. Patient-reported outcomes in cancer care - hearing the patient voice at greater volume. Nat Rev Clin Oncol. 2017;14(12):763–72. https://doi.org/10.1038/nrclinonc.2017.153.

    Article  PubMed  Google Scholar 

  32. 32.

    Wang N, Xu P, Liu Y, Zhao P, Ruan J, Zheng Y, et al. Efficacy and safety of thalidomide for chemotherapy-induced nausea and vomiting. J Cancer. 2020;11(15):4560–70. https://doi.org/10.7150/jca.45678.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Aguiar PM, de Mendonça LT, Colleoni GWB, Storpirtis S. Efficacy and safety of bortezomib, thalidomide, and lenalidomide in multiple myeloma: an overview of systematic reviews with meta-analyses. Crit Rev Oncol Hematol. 2017;113:195–212. https://doi.org/10.1016/j.critrevonc.2017.03.014.

    Article  PubMed  Google Scholar 

  34. 34.

    Bringhen S, De Wit E, Dimopoulos M-A. New Agents in Multiple Myeloma: An Examination of Safety Profiles. Clin Lymphoma Myeloma Leuk. 2017;17(7):407.e5. https://doi.org/10.1016/j.clml.2017.05.003.

    Article  Google Scholar 

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Acknowledgements

We thank all the investigators who have contributed to this study.

Funding

This study is funded by Jiangsu Hengrui Pharmaceuticals Co., Ltd. which is the inventor and producer of pyrotinib. The sponsor will have the opportunity to prospectively review any proposed publication, abstract or other type of disclosure that reports the results of the study. The sponsor will not change the conclusions and content of any publication or presentation. In any case, the sponsor will not unreasonably withhold publication to the benefit of science and/or common interest.

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Authors

Contributions

SL as principle investigator was involved in the study conception and design; XA, HJ, ZZ, ZC, YY and ZL will be involved in the acquisition of data; XA, ZS, HJ, ZZ, ZC, YY and ZL will be involved in the analysis and interpretation of data; XA were involved in drafting the manuscript; and XA and ZS were involved in revising the manuscript. All authors have read and approved the final version of manuscript.

Corresponding author

Correspondence to Shun Lu.

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Ethics approval and consent to participate

The study has been approved by the ethics committee of Shanghai Chest Hospital (No. LS2003). Written informed consent is obtained from each participant before enrollment.

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The authors declare that they have no competing interests.

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Ai, X., Song, Z., Jian, H. et al. 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. BMC Cancer 21, 1033 (2021). https://doi.org/10.1186/s12885-021-08759-8

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Keywords

  • Pyrotinib
  • Thalidomide
  • Non-small-cell lung cancer
  • Human epidermal growth factor receptor 2
  • Protocol