PECATI: A Multicentric, Open-Label, Single-Arm Phase II Study to Evaluate the Efficacy and Safety of Pembrolizumab and Lenvatinib in Pretreated B3-Thymoma and Thymic Carcinoma Patients

Current trial report PECATI: A Multicentric, Open-Label, Single-Arm Phase II Study to Evaluate the Efficacy and Safety of Pembrolizumab and Lenvatinib in Pretreated B3-Thymoma and Thymic Carcinoma Patients Jordi Remon, 1 Nicolas Girard, 2 Silvia Novello, 3 Javier de Castro, 4 Laurence Bigay-Game, 5 Reyes Bernabé, 6 Laurent Greillier, 7 Joaquin Mosquera, 8 Sophie Cousin, 9 Oscar Juan, 10 Miguel Sampayo, 11 Benjamin Besse 12 , 13 Abstract Thymic epithelial tumors are rare neoplastic proliferations of thymic epithelial cells. The aggressiveness of these malignancies increases as higher is the histologic subtype, being thymic carcinoma the most aggressive subtype, with a greater tendency to metastatic spread. In metastatic setting, there is no standard treatment after progression on platinumbased chemotherapy. In this scenario, monotherapy treatment either with lenvatinib, a multi-tyrosine kinase inhibitor with antiangiogenic properties, or pembrolizumab, an immune-checkpoint inhibitor, has reported clinical activity. Potential combination of both agents may have synergistic activity as reported in other cancer types. PECATI trial is a singlearm, investigator-initiated phase II study aiming to assess the activit y and safet y of the combination of lenvatinib and pembrolizumab in 43 patients with advanced B3-thymoma or thymic carcinoma who progressed on or after at least one previous line of platinum-based chemotherapy. The primary endpoint of the trial is 5-month progression-free survival rate and the secondary endpoints include overall response rate, duration of response, and overall survival. Clinical Lung Cancer, Vol. 23, No. 3, e243–e246 © 2021 Elsevier Inc. All rights reserved. Keywords: Thymic epithelial tumors, Immunotherapy, Second-line, Pembrolizumab, Lenvatinib 1 Department of Medical Oncology, Centro Integral Oncológico Clara Campal (HM-CIOCC), Hospital HM Delfos, HM Hospitales, Barcelona, Spain 2 Institut du thorax Curie Montsouris, Institut Curie Paris France UVSQ, Paris Saclay University, Paris, France 3 Department of Oncology, University of Turin, S. Luigi Gonzaga Hospital, Orbassano, TO, Italy 4 Department of Medical Oncology, Hospital La Paz, Madrid, Spain 5 Department of Pneumology, Centre Hospitalier Universitaire de Toulousse, Toulouse, France 6 Department of Medical Oncology, Hospital Virgen del Rocío, Seville, Spain 7 Aix Marseille Univ, APHM, INSERM, CNRS, CRCM, Hôpital du Nord, Multidisciplinary Oncology and Therapeutic Innovations Department, Marseille, France 8 Department of Medical Oncology, Hospital Universitario de la Coruña, La Coruña, Spain 9 Department of Pneumology, Institute Bergonié, France 10 Department of Medical Oncology, Hospital La Fe, Valencia, Spain 11 Medica Scientia Innovation Research (MEDSIR), Barcelona, Spain 12 Department of Cancer Medicine, Gustave Roussy, Villejuif, France 13 Université Paris-Saclay, Orsay, France. Submitted: Jun 14, 2021; Accepted: Jul 4, 2021; Epub: 20 July 2021 Address for correspondence: Jordi Remon, MD, PhD, Medical Oncology Department, Centro Integral Oncológico Clara Campal (HM-CIOCC) Barcelona, HM Delfos; Avinguda de Vallcarca, 151, 08023 Barcelona, Spain. E-mail contact: [email protected] Introduction Thymic epithelial tumors (TETs) are rare neoplastic proliferations of thymic epithelial cells, which are classified according to the World Health Organization as thymomas A, AB, B1, B2, B3, and thymic carcinoma (TC). 1 The aggressiveness of these malignancies increases as higher is the histologic subtype, being TC the most aggressive subtype, with a greater tendency to metastatic spread. At baseline, the diagnostic of metastatic disease is more common in B3- thymoma and TC than in other TET subtypes. 2 Finally, autoimmune disorders (AID) may occur in up to one-third of patients with TETs, mainly in thymoma and being very uncommon in TC ( < 5%). Myasthenia gravis is the most common AID associated with TETs, although other AIDs have been reported. 3 Although platinum-based chemotherapy is the accepted standard-of-care treatment in first-line setting, 4 standard secondline treatment is not yet defined, and different strategies have been tested (such as everolimus, pemetrexed, or etoposide), 5-7 which may impact in patients’ outcome. 8 So far, no drugs are approved by the FDA or the EMA specifically for TET. Vascular endothelial growth factor signaling plays a crucial role in TC cell physiopathology as 1525-7304/$ - see front matter © 2021 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.cllc.2021.07.008 Clinical Lung Cancer May 2022 e243 PECATI well as microvessel density, both correlated with invasiveness and advanced stage. 9 In 2 single-arm phase II trials, the multi-tyrosine kinase inhibitors with antiangiogenic properties sunitinib and lenvatinib have reported meaningful activity in previously treated patients with TC, achieving a response rate ranging from 26% to 38% and a median progression-free survival (PFS) of up to 9.3 months. 10 , 11 Both agents are accepted as potential treatment approaches in TCs with progression after at least one previous line of platinum-based chemotherapy. Recently, immune-checkpoint inhibitors (ICI) have also been tested in pretreated patients with TETs. Globally, pembrolizumab, 12-14 nivolumab, 15 and avelumab 16 have reported clinical activity in this population. Specifically, pembrolizumab in TCs has yielded a response rate of 22.5% with a median overall survival (OS) of 25.4 months, and up to 20% of patients are alive at 5 years after treatment initiation. 12 , 13 Although ICI may represent a new therapeutic approach in patients with TET, it is not yet a standard strategy. Indeed, the benefit must be balanced with risk of grade 3-4 immune-related adverse events, especially in patients with thymoma due to the association with AID. 12 , 14 Therefore, immune-strategy should be limited to patients with TC and B3-thymoma after ruling out AID for minimizing toxicity profile. The angiogenic factors inhibit immune cells and induce immune suppression at multiple levels, but antiangiogenic agents may enhance the efficacy of ICI. 17 Therefore, the combination of ICI and antiangiogenics is an attractive and novel approach that may provide greater antitumor activity than either single-agent alone. Indeed the combination of pembrolizumab and lenvatinib has reported activity in other malignancies. 18 , 19 Therefore, based on these premises and that both drugs, lenvatinib and pembrolizumab, have reported meaningful clinical activity as monotherapy in TETs, we designed the PECATI trial with the aim to investigate the activity and safety of the combination of lenvatinib and pembrolizumab in patients with advanced B3-thymoma or TC who progressed on or after at least one previous line of platinum-based chemotherapy. Patients and Methods Study Design PECATI (ClinicalTrials.gov identifier, NCT04710628) is an international, multicentric, open-label, single-arm, investigatorinitiated phase II trial enrolling previously treated patients with metastatic B3-Thymoma and TC, regardless of programmed deathligand 1 (PD-L1) expression. The main selection criteria are described in Table 1 . The study design is summarized in Figure 1 . Eligible patients will receive lenvatinib (20 mg orally once daily) and pembrolizumab (200 mg intravenously on day 1 of each 21- day cycle). Study treatment will continue until clinical or radiological disease progression, unacceptable toxicity according to the treating physician or patient refusal. In case of withdrawal of any of the agents due to toxicity, continuation in monotherapy will be allowed as per investigator’s criteria, and the maximum duration of treatment with pembrolizumab with or without lenvatinib will be 35 cycles (2 years). Study Objectives The primary objective is to evaluate the efficacy of the combination in terms of 5-month PFS rate (according to the Response Evaluation Criteria In Solid Tumors version 1.1), which is defined as the proportion of patients with B3-thymoma and TC without disease progression or death due to any cause within the first 5 months after treatment initiation. Radiological tumor assessment will be performed at weeks 6 and 12, then every 9 weeks during the first 12 months, and every 12 weeks thereafter. The secondary efficacy endpoints are to evaluate overall response rate, disease control rate, duration of response, and OS. Additional secondary endpoint includes safety and toxicity profile of the combination according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v.5.0). Although PECATI study includes exploratory objectives, these will be performed outside the scope of current protocol. In this subsequent translational research, we aim to retrospectively evaluate: • PD-L1 expression by immunohistochemistry (22C3 anti-PD-L1 monoclonal antibody assay) with the aim to define an optimal cut-off value; • Blood tumor mutational burden by next-generation sequencing at baseline and at the time of disease progression or end of study; • Genomic profile by next-generation sequencing through a liquid biopsy test at baseline and at the time of disease progression or end of study. Statistical Analysis In the PECATI trial we plan to recruit a total of 43 patients in 15 months. The sample size assumed an arcsine square root transformed confidence intervals (CIs) based on Kaplan–Meier estimator. We hypothesize that excluding a 5-month PFS rate less than or equal to 50% (null hypothesis), while targeting an improvement of 5- month PFS rate greater than or equal to 68.6% (alternative hypothesis) would be an optimal approach to evaluate the clinical activity of pembrolizumab plus lenvatinib combination. The sample size of 43 patients is necessary to attain 80% power at nominal level of onesided alpha of 0.05. The analysis will be performed with exponential maximum likelihood estimation test. Efficacy and safety data will be assessed in the full analysis set that included all patients who received at least one dose of the combination. The PFS, duration of response, and OS will be estimated with the Kaplan–Meier method. The time-to-event endpoints will be compared between patient characteristic with Cox regression models. Clopper-Pearson 95% CIs will be used to estimate the rates of patients with overall response and disease control. These efficacy endpoints will be compared between patient characteristic with logistic regression models. For secondary and subgroup analyses, we will use 2 P values with αlevel of significance of .05 or less. Conclusion The PECATI trial gives the opportunity to test the combination of lenvatinib plus pembrolizumab, two drugs showing promising efficacy as monotherapy in TETs, in previously treated advanced patients with B3-thymoma and TC. The PECATI trial will be e244 Clinical Lung Cancer May 2022 Jordi Remon et al Table 1 Main Selection Criteria Main inclusion Criteria Main exclusion Criteria • Histological diagnosis of metastatic/recurrent B3-thymoma or thymic carcinoma • Previous therapy with immune-strategy or sunitinib (prior bevacizumab-based therapy is allowed) • Radiological disease progression on or after at least one line of platinum-based chemotherapy • Presence of untreated central nervous system metastases • Presence of measurable disease according to the Response Evaluation Criteria In Solid Tumors (RECIST) version (v.)1.1 criteria • Uncontrolled or poorly controlled hypertension despite standard medical therapy, significant cardiovascular impairment or fraction ejection < 50% • Negative result for Myasthenia Gravis by acetylcholine receptor antibodies test • Intratumor cavitation, direct invasion of main mediastinal blood vessels by the tumor or exist previous bleeding • Age ≥18 years of age • Active autoimmune disease • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 • Has an intestinal disease not allowing swallowing pills • Availability of archived or fresh histological material Figure 1 PECATI study design. •Metastac B3-thymoma or thymic carcinoma •At least one previous line of planum-based chemotherapy •No autoimmune disorders •Measurable disease •No: intratumor cavitaon, invasion of blood vessels, previous bleeding •ECOG PS 0-1 LENVATINIB 20 mg orally daily + PEMBROLIZUMAB 200 mg IV D1 every 3 weeks unl PD or up to 2 years Subgroup analysis: •Histologic subtype: B3-T vs. TC •Previous lines: ≤ 1 vs. > 1 •PD-L1 (22C3): ≥ 50% vs. < 50% Primary Endpoint: •5-month Progression-Free Survival as per RECIST v.1.1. Secondary Endpoints: •Overall response rate, Disease control rate, Duraon of response, Maximum tumor shrinkage as per RECIST v.1.1. •Overall survival. •Safety and tolerability as per CTCAE v.5.0. Stascal assumpons: •P0= 50% •P1= 68.6% •Alfa: 5%, Beta: 20% Countries where PECATI trial will be conducted N=43 pts conducted in 10 hospitals in 3 European countries (Spain, France, and Italy), giving access to innovative strategies to these patients and improving clinical research in this rare malignancy. Indeed, the results of PECATI trial may help to endorse the immune strategy in TET, which is being also tested in other ongoing clinical trials either as monotherapy (NCT03076554, NCT04321330, NCT04469725, NCT04417660, NCT03134118) or in combination (NCT03134118, NCT03463460, and CAVEATT trial). Disclosure The authors have stated that they have no conflicts of interest. Acknowledgments The present study is funded by a grant by Merck-Sharpe & Dohme (MSD). The study drugs pembrolizumab and lenvatinib are provided by MSD. Supplementary materials Supplementary material associated with this article can be found, in the online version, at doi: 10.1016/j.cllc.2021.07.008 . References 1. Marx A, Chan JKC, Coindre J-M, et al. The 2015 World Health Organization classification of tumors of the thymus: continuity and changes. J Thorac Oncol . 2015;10:1383–1395. doi: 10.1097/JTO.0000000000000654 . 2. Weis C-A, Yao X, Deng Y, et al. The impact of thymoma histotype on prognosis in a worldwide database. J Thorac Oncol . 2015;10:367–372. doi: 10.1097/JTO. 0000000000000393 . 3. Montanez JCB, Boucher M-É, Dansin E, et al. Autoimmune diseases in centrally reviewed thymic epithelial tumours (TET). Ann Oncol . 2020;31:S1078. doi: 10. 1016/j.annonc.2020.08.1442 . 4. Gbolahan OB, Porter RF, Salter JT, et al. A phase II study of pemetrexed in patients with recurrent thymoma and thymic carcinoma. J Thorac Oncol . 2018;13:1940– 1948. doi: 10.1016/j.jtho.2018.07.094 . 5. Zucali PA, De Pas T, Palmieri G, et al. Phase II study of everolimus in patients with thymoma and thymic carcinoma previously treated with cisplatin-based chemotherapy. J Clin Oncol . 2018;36:342–349. doi: 10.1200/JCO.2017.74.4078 . Clinical Lung Cancer May 2022 e245 PECATI 6. Bluthgen MV, Boutros C, Fayard F, Remon J, Planchard D, Besse B. Activity and safety of oral etoposide in pretreated patients with metastatic or recurrent thymic epithelial tumors (TET): a single-institution experience. Lung Cancer Amst Neth . 2016;99:111–116. doi: 10.1016/j.lungcan.2016.06.020 . 7. Gbolahan OB, Porter RF, Salter JT, et al. A phase II study of pemetrexed in patients with recurrent thymoma and thymic carcinoma. J Thorac Oncol . 2018;13:1940– 1948. doi: 10.1016/j.jtho.2018.07.094 . 8. Merveilleux du Vignaux C, Dansin E, Mhanna L, et al. Systemic therapy in advanced thymic epithelial tumors: insights from the RYTHMIC prospective cohort. J Thorac Oncol . 2018;13:1762–1770. doi: 10.1016/j.jtho.2018.08.005 . 9. Tomita M, Matsuzaki Y, Edagawa M, et al. Correlation between tumor angiogenesis and invasiveness in thymic epithelial tumors. J Thorac Cardiovasc Surg . 2002;124:493–498. doi: 10.1067/mtc.2002.124389 . 10. Thomas A, Rajan A, Berman A, et al. Sunitinib in patients with chemotherapyrefractory thymoma and thymic carcinoma: an open-label phase 2 trial. Lancet Oncol . 2015;16:177–186. doi: 10.1016/S1470- 2045(14)71181- 7 . 11. Sato J, Satouchi M, Itoh S, et al. Lenvatinib in patients with advanced or metastatic thymic carcinoma (REMORA): a multicentre, phase 2 trial. Lancet Oncol . 2020;21:843–850. doi: 10.1016/S1470- 2045(20)30162- 5 . 12. Giaccone G, Kim C, Thompson J, et al. Pembrolizumab in patients with thymic carcinoma: a single-arm, single-centre, phase 2 study. Lancet Oncol . 2018;19:347– 355. doi: 10.1016/S1470- 2045(18)30062- 7 . 13. Giaccone G, Kim C. Durable response in patients with thymic carcinoma treated with pembrolizumab after prolonged follow-up. J Thorac Oncol . 2021;16:483–485. doi: 10.1016/j.jtho.2020.11.003 . 14. Cho J, Kim HS, Ku BM, et al. Pembrolizumab for patients with refractory or relapsed thymic epithelial tumor: an open-label phase II trial. J Clin Oncol . 2019;37:2162–2170. doi: 10.1200/JCO.2017.77.3184 . 15. Katsuya Y, Horinouchi H, Seto T, et al. Single-arm, multicentre, phase II trial of nivolumab for unresectable or recurrent thymic carcinoma: PRIMER study. Eur J Cancer Oxf Engl 1990 . 2019;113:78–86. doi: 10.1016/j.ejca.2019.03.012 . 16. Rajan A, Heery CR, Thomas A, et al. Efficacy and tolerability of anti-programmed death-ligand 1 (PD-L1) antibody (Avelumab) treatment in advanced thymoma. J Immunother Cancer . 2019;7:269. doi: 10.1186/s40425- 019- 0723- 9 . 17. Fukumura D, Kloepper J, Amoozgar Z, Duda DG, Jain RK. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol . 2018;15:325–340. doi: 10.1038/nrclinonc.2018.29 . 18. Motzer R, Alekseev B, Rha S-Y, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med . 2021;384:1289–1300. doi: 10.1056/NEJMoa2035716 . 19. Makker V, Taylor MH, Aghajanian C, et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer. J Clin Oncol . 2020;38:2981–2992. doi: 10.1200/JCO.19.02627 . e246 Clinical Lung Cancer May 2022